Heterocyclic compounds as nav channel inhibitors and uses thereof

ABSTRACT

The present invention relates to heterocyclic compounds, and pharmaceutically acceptable compositions thereof, useful as Nav1.6 inhibitors.

RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application61/945,227, filed on Feb. 27, 2014, the contents of which are hereinincorporated in its entirety by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to heterocyclic compounds that are usefulas inhibitors of NaV1.6. The invention also provides pharmaceuticallyacceptable compositions comprising compounds of the present inventionand methods of using said compositions in the treatment of variousdisorders.

BACKGROUND OF THE INVENTION

Mechanistics studies on white matter damage have shown that exposure ofaxons to hypoxia leads to excessive sodium influx and a consequentinverse functioning of the sodium-calcium exchanger (NCX) thatultimately triggers activation of calcium-mediated cell death cascades.Experimentally, this idea is supported by a large body of experimentalobservations including that blocking of sodium channels withTetrodotoxin (TTX) or saxitosin, blocking of the NCX (with bepridil,benzamil, dichlorobenzamil) or manipulation of the transmembrane sodiumgradient by substituting Na⁺ with Li⁺ or choline can all protect axonsagainst anoxic injury. Conversely, increasing sodium channelpermeability during anoxia with veratridine resulted in greater injury.Under hypoxic conditions, the availability of adenosine triphosphate(ATP) within is axoplasm becomes limited not only due to decreasesynthesis but also due to the increased demands from thesodium-potassium adenosine triphosphatase (Na⁺/K⁺-ATPase) for extrudingexceeding sodium. It has also been shown that in an inflammatory milieu,where nitric oxide (NO) and reactive oxygen species (ROS) are producedby phagocytic cells such as macrophages and microglia, the availabilityof ATP is diminished by the damage that this mediators can directlycause on mitochondria, particularly on enzymes involved in the synthesisof ATP itself. Through this mechanism, NO donors can exacerbate theaxonal damage induced by hypoxia. Indeed, in multiple sclerosis, where apersistent sodium current is hypothesized to overload demyelinated axonsand where the synthesis of ATP is affected by NO and reactive oxygenspecies (ROS) due to the inflammatory nature of this disease, anyinitial Na⁺ overload cannot be overcome and creates a vicious cycle,causing reverse functioning of the NCX which in turn activatesCa⁺²-mediated cell cascades including the increased synthesis of NO,which besides impairing ATP synthesis itself, in addition to triggeringaxonal degeneration and apoptosis by multiple known mechanisms. Thisaspect of the pathology of multiple sclerosis is well documented in theliterature and has been named virtual hypoxia.

In line with the hypothesis of the association of sodium overload andaxonal degeneration in multiple sclerosis are the observations ofincreased total sodium content in the advanced stage ofrelapsing-remitting (RR) multiple sclerosis, especially in thenormal-appearing brain tissues by using sodium 23 (23Na) magneticresonance (MR) imaging. Sodium channel blockers such as Phenytoin,Carbamazepine, Flecainide and Lamotrigine are well established drugs andare indicated for different conditions such as epilepsy, neuropathicpain and arrhythmia. All these compound have one feature in common,i.e., they are all state-dependent sodium channel blockers, meaning thatthey do not affect the normal functioning of sodium channels, but do soparticularly in pathological states where higher than normal neuronalfiring increases the proportion of channels that are found at any timepoint in a conformational configuration called inactivated state. Thisis crucial for the safety of these drugs given that action potentials inthe central and peripheral nervous systems (CNS and PNS) and axons areconducted by voltage-gated sodium channels.

All of the above mentioned examples of VGSC blockers have been tested inEAE and have in general been shown to improve clinical scores,ameliorate the axonal loss and demyelination associated with disease andrevert the loss in axonal conductivity in the spinal cord of the testanimals. Voltage-gated sodium channel blockers also exhibit a protectiveeffect in other disease models including spinal cord injury which is arelevant CNS injury model. Collectively, the body of evidence discussedabove was convincing enough to raise interest within the scientificcommunity to test the efficacy of VGSC as neuroprotective agents andLamotrigine was tested in a randomised, double-blind phase II clinicaltrial for neuroprotection in secondary progressive MS patients andLamotrigine treatment reduced the deterioration of the timed 25-footwalk (p=0.02) over 2 years.

Two voltage-gated sodium channel (VGSC) isoforms namely Nav1.2 andNav1.6 have been shown to be overexpressed in post-morten tissue frommultiple sclerosis patients and in different animal models mimicking thedisease and that are collectively known as experimental autoimmuneencephalomyelitis (EAE). Amongst neurons overexpressing VGSC, thoseoverexpressing Nav1.6 are more frequently co-localized with thedegeneration marker β-amyloid precursor protein (APP) than thoseoverexpressing Nav1.2. Indeed, it has long been known that axonsselectively expressing Nav1.2 are extremely resistant to anoxic injury.This is likely related to the electrophysiological properties of thischannel: Nav1.2 shows greater accumulation of inactivation at highfrequencies of stimulation while producing smaller persistent currentsin comparison with Nav1.6. On the other hand, Nav1.6 produces largepersistent currents that may play a role in triggering reversefunctioning of the NCX which can injure demyelinated axons where Nav1.6and the NCX are co-localized. Collectively, this evidence indicates thatthe Nav1.6 isoform mediates axonal degeneration in multiple sclerosis.

SUMMARY OF THE INVENTION

In one aspect, the invention provides for compounds of formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, wherein each of Z¹, Z², X, A, Y, ring B, R¹, R², R³, R⁴, R⁵, m,n, q, and r, is as defined and described in embodiments herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with NaV1.6. Such diseases,disorders, or conditions include those described herein.

FIGURES

FIG. 1—Command Voltage

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCompounds of the Invention

In certain aspects, the present invention provides for inhibitors ofNaV1.6. In some embodiments, such compounds include those of theformulae described herein, or a pharmaceutically acceptable salt,solvate, hydrate, or polymorph thereof, wherein each variable is asdefined and described herein.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Exemplary aliphatic groups are linear or branched, substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl groups andhybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, orphosphorus (including, any oxidized form of nitrogen, sulfur, orphosphorus; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic andbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains three to seven ring members. The term “aryl”is used interchangeably with the term “aryl ring”. In certainembodiments of the present invention, “aryl” refers to an aromatic ringsystem. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyland the like, which optionally includes one or more substituents. Alsoincluded within the scope of the term “aryl”, as it is used herein, is agroup in which an aromatic ring is fused to one or more non-aromaticrings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group is optionally mono- or bicyclic. The term “heteroaryl”is used interchangeably with the terms “heteroaryl ring”, “heteroarylgroup”, or “heteroaromatic”, any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl),or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclicgroup”, “heterocyclic moiety”, and “heterocyclic radical”, are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group is optionally mono- or bicyclic.The term “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, certain compounds of the invention contain“optionally substituted” moieties. In general, the term “substituted”,whether preceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. “Substituted” applies to one or more hydrogens that areeither explicit or implicit from the structure

refers to at least

refers to at least

Unless otherwise indicated, an “optionally substituted” group has asuitable substituent at each substitutable position of the group, andwhen more than one position in any given structure is substituted withmore than one substituent selected from a specified group, thesubstituent is either the same or different at every position.Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds. The term “stable”, as used herein, refers to compounds thatare not substantially altered when subjected to conditions to allow fortheir production, detection, and, in certain embodiments, theirrecovery, purification, and use for one or more of the purposesdisclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently deuterium; halogen;—(CH₂)₀₋₄R^(o); —(CH₂)₀₋₄OR^(o); —O(CH₂)₀₋₄R^(o), —O—(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄CH(OR^(o))₂; —(CH₂)₀₋₄SR^(o); —(CH₂)₀₋₄Ph, which are optionallysubstituted with R^(o); —(CH₂)₀₋₄O(CH₂)₀₋Ph which is optionallysubstituted with R^(o); —CH═CHPh, which is optionally substituted withR^(o); —(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which is optionally substituted withR^(o); —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R^(o))₂; —(CH₂)₀₋₄N(R^(o))C(O)R^(o);—N(R^(o))C(S)R^(o); —(CH₂)₀₋₄N(R^(o))C(O)NR₂; —N(R^(o))C(S)NR^(o) ₂;—(CH₂)₀₋₄N(R^(o))C(O)OR^(o); —N(R^(o))N(R^(o))C(O)R^(o);—N(R^(o))N(R^(o))C(O)NR^(o) ₂; —N(R^(o))N(R^(o))C(O)OR^(o);—(CH₂)₀₋₄C(O)R^(o); —C(S)R^(o); —(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄C(O)SR^(o); —(CH₂)₀₋₄C(O)OSiR^(o) ₃; —(CH₂)₀₋₄OC(O)R^(o);—OC(O)(CH₂)₀₋₄SR^(o), SC(S)SR^(o); —(CH₂)₀₋₄SC(O)R^(o);—(CH₂)₀₋₄C(O)NR^(o) ₂; —C(S)NR^(o) ₂; —C(S)SR^(o); —SC(S)SR^(o),—(CH₂)₀₋₄OC(O)NR^(o) ₂; —C(O)N(OR^(o))R^(o); —C(O)C(O)R^(o);—C(O)CH₂C(O)R^(o); —C(NOR^(o))R^(o); —(CH₂)₀₋₄SSR^(o);—(CH₂)₀₋₄S(O)₂R^(o); —(CH₂)₀₋₄S(O)₂OR^(o); —(CH₂)₀₋₄OS(O)₂R^(o);—S(O)₂NR^(o) ₂; —(CH₂)₀₋₄S(O)R^(o); —N(R^(o))S(O)₂NR^(o) ₂;—N(R^(o))S(O)₂R^(o); —N(OR^(o))R^(o); —C(NH)NR^(o) ₂; —P(O)₂R^(o);—P(O)R^(o) ₂; —OP(O)R^(o) ₂; —OP(O)(OR^(o))₂; SiR^(o) ₃; —(C₁₋₄ straightor branched alkylene)O—N(R^(o))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(o))₂, wherein each R^(o) is optionally substitutedas defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁ Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(o), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which is optionally substituted as definedbelow.

Suitable monovalent substituents on R^(o) (or the ring formed by takingtwo independent occurrences of R^(o) together with their interveningatoms), are independently deuterium, halogen, —(CH₂)₀₋₂R^(),-(haloR^()), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(), —(CH₂)₀₋₂CH(OR^())₂;—O(haloR^()), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(), —(CH₂)₀₋₂C(O)OH,—(CH₂)₀₋₂C(O)OR^(), —(CH₂)₀₋₂SR^(), —(CH₂)₀₋₂SH, —(CH₂)₀₋ ₂NH₂,—(CH₂)₀₋₂NHR^(), —(CH₂)₀₋₂NR^() ₂, —NO₂, —SiR^() ₃, —OSiR^() ₃,—C(O)SR^(), —(C₁₋₄ straight or branched alkylene)C(O)OR^(), or—SSR^() wherein each R^() is unsubstituted or where preceded by “halo”is substituted only with one or more halogens, and is independentlyselected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. Suitabledivalent substituents on a saturated carbon atom of R^(o) include ═O and═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which is substituted as defined below, oran unsubstituted 5-6-membered saturated, partially unsaturated, or arylring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which is optionally substitutedas defined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(), -(haloR^()), —OH, —OR^(), —O(haloR^()), —CN, —C(O)OH,—C(O)OR, —NH₂, —NHR^(), —NR^() ₂, or —NO₂, wherein each R^() isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which is optionallysubstituted as defined below, unsubstituted —OPh, or an unsubstituted5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(), -(haloR^()), —OH, —OR^(), —O(haloR^()), —CN,—C(O)OH, —C(O)OR^(), —NH₂, —NHR^(), —NR^() ₂, or —NO₂, wherein eachR^() is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain embodiments, the terms “optionally substituted”, “optionallysubstituted alkyl,” “optionally substituted “optionally substitutedalkenyl,” “optionally substituted alkynyl”, “optionally substitutedcarbocyclic,” “optionally substituted aryl”, “optionally substitutedheteroaryl,” “optionally substituted heterocyclic,” and any otheroptionally substituted group as used herein, refer to groups that aresubstituted or unsubstituted by independent replacement of one, two, orthree or more of the hydrogen atoms thereon with typical substituentsincluding, but not limited to:

—F, —Cl, —Br, —I, deuterium,

—OH, protected hydroxy, alkoxy, oxo, thiooxo,

—NO₂, —CN, CF₃, N₃,

—NH₂, protected amino, —NH alkyl, —NH alkenyl, —NH alkynyl, —NHcycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocyclic, -dialkylamino,-diarylamino, -diheteroarylamino,

—O— alkyl, —O— alkenyl, —O— alkynyl, —O— cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocyclic,

—C(O)— alkyl, —C(O)— alkenyl, —C(O)— alkynyl, —C(O)— carbocyclyl,—C(O)-aryl, —C(O)— heteroaryl, —C(O)-heterocyclyl,

—CONH₂, —CONH— alkyl, —CONH— alkenyl, —CONH— alkynyl, —CONH-carbocyclyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocyclyl,

—OCO₂— alkyl, —OCO₂— alkenyl, —OCO₂— alkynyl, —OCO₂— carbocyclyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocyclyl, —OCONH₂, —OCONH—alkyl, —OCONH— alkenyl, —OCONH— alkynyl, —OCONH— carbocyclyl, —OCONH—aryl, —OCONH— heteroaryl, —OCONH— heterocyclyl,

—NHC(O)— alkyl, —NHC(O)— alkenyl, —NHC(O)— alkynyl, —NHC(O)—carbocyclyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocyclyl,—NHCO₂— alkyl, —NHCO₂— alkenyl, —NHCO₂— alkynyl, —NHCO₂— carbocyclyl,—NHCO₂— aryl, —NHCO₂— heteroaryl, —NHCO₂-heterocyclyl, —NHC(O)NH₂,—NHC(O)NH— alkyl, —NHC(O)NH— alkenyl, —NHC(O)NH— alkenyl, —NHC(O)NH—carbocyclyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH—heterocyclyl, NHC(S)NH₂, —NHC(S)NH— alkyl, —NHC(S)NH— alkenyl,—NHC(S)NH— alkynyl, —NHC(S)NH— carbocyclyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocyclyl, —NHC(NH)NH₂, —NHC(NH)NH—alkyl, —NHC(NH)NH— alkenyl, —NHC(NH)NH— alkenyl, —NHC(NH)NH—carbocyclyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH—heterocyclyl, —NHC(NH)— alkyl, —NHC(NH)— alkenyl, —NHC(NH)— alkenyl,—NHC(NH)— carbocyclyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocyclyl,

—C(NH)NH— alkyl, —C(NH)NH— alkenyl, —C(NH)NH— alkynyl, —C(NH)NH—carbocyclyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl, —C(NH)NH-heterocyclyl,

—S(O)— alkyl, —S(O)— alkenyl, —S(O)— alkynyl, —S(O)— carbocyclyl,—S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocyclyl —SO₂NH₂, —SO₂NH— alkyl,—SO₂NH— alkenyl, —SO₂NH— alkynyl, —SO₂NH— carbocyclyl, —SO₂NH— aryl,—SO₂NH— heteroaryl, —SO₂NH— heterocyclyl,

—NHSO₂— alkyl, —NHSO₂— alkenyl, —NHSO₂— alkynyl, —NHSO₂— carbocyclyl,—NHSO₂-aryl, —NHSO₂-heteroaryl, —NHSO₂-heterocyclyl,

—CH₂NH₂, —CH₂SO₂CH₃,

-mono-, di-, or tri-alkyl silyl,

-alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl,-heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic,-heterocyclic, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy,-methoxyethoxy, —SH, —S— alkyl, —S— alkenyl, —S— alkynyl, —S—carbocyclyl, —S-aryl, —S-heteroaryl, —S-heterocyclyl, ormethylthiomethyl.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. Representative alkalior alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. In some embodiments, the groupcomprises one or more deuterium atoms.

There is furthermore intended that a compound of the formula I includesisotope-labeled forms thereof. An isotope-labeled form of a compound ofthe formula I is identical to this compound apart from the fact that oneor more atoms of the compound have been replaced by an atom or atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the atom which usually occurs naturally. Examples ofisotopes which are readily commercially available and which can beincorporated into a compound of the formula I by well-known methodsinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phos-phorus,fluo-rine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O,³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶CI, respectively. A compound of the formula I,a prodrug, thereof or a pharmaceutically acceptable salt of either whichcontains one or more of the above-mentioned isotopes and/or otherisotopes of other atoms is intended to be part of the present invention.An isotope-labeled compound of the formula I can be used in a number ofbeneficial ways. For example, an isotope-labeled compound of the formulaI into which, for example, a radioisotope, such as ³H or ¹⁴C, has beenincorporated, is suitable for medicament and/or substrate tissuedistribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to simple preparationand excellent detectability. Incorporation of heavier isotopes, forexample deuterium (²H), into a compound of the formula I has therapeuticadvantages owing to the higher metabolic stability of thisisotope-labeled compound. Higher metabolic stability translates directlyinto an increased in vivo half-life or lower dosages, which under mostcircumstances would represent a preferred embodiment of the presentinvention. An isotope-labeled compound of the formula I can usually beprepared by carrying out the procedures disclosed in the synthesisschemes and the related description, in the example part and in thepreparation part in the present text, replacing a non-isotope-labeledreactant by a readily available isotope-labeled reactant.

Deuterium (²H) can also be incorporated into a compound of the formula Ifor the purpose in order to manipulate the oxidative metabolism of thecompound by way of the primary kinetic isotope effect. The primarykinetic isotope effect is a change of the rate for a chemical reactionthat results from exchange of isotopic nuclei, which in turn is causedby the change in ground state energies necessary for covalent bondformation after this isotopic exchange. Exchange of a heavier isotopeusually results in a lowering of the ground state energy for a chemicalbond and thus causes a reduction in the rate in rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a com-poundof the formula I that is susceptible to oxidation, the profile of thiscompound in vivo can be drastically modified and result in improvedpharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art is able to optimize pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula I with improved stability throughresistance to such oxidative metabolism. Significant improvements in thepharmacokinetic profiles of compounds of the formula I are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t/2), concentration at maximum therapeutic effect(Cm), area under the dose response curve (AUC), and F; and in terms ofreduced clearance, dose and materials costs.

The following is intended to illustrate the above: a compound of theformula I which has multiple potential sites of attack for oxidativemetabolism, for example benzylic hydrogen atoms and hydrogen atomsbonded to a nitrogen atom, is prepared as a series of analogues in whichvarious combinations of hydrogen atoms are replaced by deuterium atoms,so that some, most or all of these hydrogen atoms have been replaced bydeuterium atoms. Half-life determinations enable favorable and accuratedetermination of the extent of the extent to which the improvement inresistance to oxidative metabolism has improved. In this way, it isdetermined that the half-life of the parent compound can be extended byup to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of the formula I can also beused to achieve a favorable modification of the metabolite spectrum ofthe starting compound in order to diminish or eliminate undesired toxicmetabolites. For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

As used herein, the term “modulator” is defined as a compound that bindsto and/or inhibits the target with measurable affinity. In certainembodiments, a modulator has an IC₅₀ and/or binding constant of greaterthan about 20 μM, between about 10 μM and 20 μM, or less than about 10μM. In certain embodiments, a modulator has an IC₅₀ and/or bindingconstant of greater than about 5 μM, between about 1 M and 5 μM, or lessthan about 1 μM.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

3. Description of Exemplary Compounds

According to one aspect, the present invention provides a compound offormula I,

or a pharmaceutically acceptable salt, solvate, hydrate, or polymorphthereof, wherein:

-   Z¹ is C(R)(R), C(O), C(S), or C(NR);-   Z² is C(R)(R), O, S, SO, SO₂, or NR;-   X is —O—, —S—, —SO₂—, —SO—, —C(O)—, —CO₂—, —C(O)N(R)—, —NRC(O)—,    —NRC(O)N(R)—, —NRSO₂—, or —N(R)—; or X is absent;-   A is a C₁₋₆ aliphatic, C₅₋₁₀ aryl, a 3-8 membered saturated or    partially unsaturated carbocyclic ring, a 3-7 membered heterocylic    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur;    each of which is optionally substituted;-   R¹ is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR,    —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or    —N(R)₂;-   each of R², R³, R⁴, and R⁵, is independently H or C₁₋₆ aliphatic;-   Y is —CH₂—, —O—, —S—, —SO₂—, —SO—, —C(O)—, —CO₂—, —C(O)N(R)—,    —NRC(O)—, —NRC(O)N(R)—, —NRSO₂—, or —N(R)—;-   Ring B is C₅₋₁₀ aryl or a 5-6 membered heteroaryl ring having 1-4    heteroatoms independently selected from nitrogen, oxygen, or sulfur;    each of which is optionally substituted;-   each R⁶ is independently —R, halogen, -haloalkyl, —OR, —SR, —CN,    —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R,    —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂;-   m is 0, 1, 2, or 3;-   n is 0, 1, 2, or 3;-   q is 0, 1, 2, or 3;-   r is 1 or 2; and-   each R is independently hydrogen, C₁₋₆ aliphatic, C₅₋₁₀ aryl, a 3-8    membered saturated or partially unsaturated carbocyclic ring, a 3-7    membered heterocylic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur; each of which is    optionally substituted; or-   two R groups on the same atom are taken together with the atom to    which they are attached to form a C₃₋₁₀ aryl, a 3-8 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, Z¹ is C(R)(R). In certain embodiments, Z¹ isCH₂. In certain embodiments, Z¹ is C(O). In certain embodiments, Z¹ isC(S). In certain embodiments, Z¹ is C(NR).

In certain embodiments, Z² is C(R)(R). In certain embodiments, Z² isCH₂. In certain embodiments, Z² is O. In certain embodiments, Z² is S.In certain embodiments, Z² is SO. In certain embodiments, Z² is SO₂. Incertain embodiments, Z² is NR.

In certain embodiments, X is —O—, —S—, —SO₂—, —SO—, —C(O)—, —CO₂—,—C(O)N(R)—, —NRC(O)—, —NRC(O)N(R)—, —NRSO₂—, or —N(R)—.

In certain embodiments, X is —O—, —C(O)—, —CO₂—, or —C(O)N(R)—.

In certain embodiments, X is —O—, —C(O)—, —CO₂—, or —C(O)NH—. In certainembodiments, X is —O—. In certain embodiments, X is —C(O)—. In certainembodiments, X is —CO₂—. In certain embodiments, X is —C(O)NH—.

In certain embodiments, X is absent.

In certain embodiments, A is an optionally substituted C₁₋₆ aliphatic.

In certain embodiments, A is methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, t-butyl, straight chain or branched pentyl, or straight chainor branched hexyl; each of which is optionally substituted.

In certain embodiments, A is methyl. In certain embodiments, A is ethyl.

In certain embodiments, A is C₃₋₁₀ aryl, a 3-8 membered saturated orpartially unsaturated carbocyclic ring, a 3-7 membered heterocylic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each of whichis optionally substituted.

In certain embodiments, A is phenyl, naphthyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; 1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, A is selected from the following, each of whichis further optionally substituted:

In certain embodiments, A is selected from the following:

In certain embodiments, R¹ is H.

In certain embodiments, R¹ is —R, halogen, -haloalkyl, —OR, —SR, —CN,—NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂,—NRSO₂R, or —N(R)₂.

In certain embodiments, R¹ is C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted. In certainembodiments, R¹ is C₁₋₆ aliphatic. In certain embodiments, R¹ is methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, straight chain orbranched pentyl, or straight chain or branched hexyl; each of which isoptionally substituted. In certain embodiments, R¹ is methyl.

In certain embodiments, R¹ is halogen. In certain embodiments, R¹ is F,Cl, Br, or I. In certain embodiments, R¹ is is F or Cl. In certainembodiments, R¹ is F. In certain embodiments, R¹ is Cl.

In certain embodiments, R¹ is —OR, —SR, or —N(R)₂. In certainembodiments, R¹ is —OR. In certain embodiments, R¹ is —OH.

In various embodiments, each of R², R³, R⁴, and R⁵, is independently Hor C₁-aliphatic. In various embodiments, each of R², R³, R⁴, and R⁵, isindependently H or Me. In various embodiments, R² is H or C₁₋₆aliphatic. In various embodiments, R² is H or Me. In variousembodiments, R³ is H or C₁₋₆ aliphatic. In various embodiments, R³ is Hor Me. In various embodiments, R⁴ is H or C₁₋₆ aliphatic. In variousembodiments, R⁴ is H or Me. In various embodiments, R⁵ is H or C₁₋₆aliphatic. In various embodiments, R⁵ is H or Me.

In various embodiments, Y is —CH₂—.

In various embodiments, Ring B is C₅₋₁₀ aryl.

In various embodiments, Ring B is a 5-6 membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In various embodiments, Ring B is selected from:

In various embodiments, each R⁶ is independently —R, halogen,-haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂.

In various embodiments, each R⁶ is independently halogen, —OR, —SR,—SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R,or —N(R)₂. In various embodiments, each R⁶ is independently halogen,—OR, —SR, —SO₂R, —SOR, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂. Invarious embodiments, each R⁶ is independently halogen, —OR, —SR, —SO₂R,or —SOR.

In various embodiments, each R⁶ is independently halogen. In variousembodiments, each R⁶ is independently —OR. In various embodiments, eachR⁶ is independently —SR. In various embodiments, each R⁶ isindependently —SO₂R. In various embodiments, each R⁶ is independently—SOR.

In various embodiments, each R⁶ is independently selected from F, Cl,Br, I,

In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 0.In certain embodiments, m is 1. In certain embodiments, m is 2.

In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 0.In certain embodiments, n is 1. In certain embodiments, n is 2.

In certain embodiments, q is 0, 1, or 2. In certain embodiments, q is 0.In certain embodiments, q is 1. In certain embodiments, q is 2.

In certain embodiments, r is 1. In certain embodiments, r is 2.

In certain embodiments, each of Z¹, Z², X, A, Y, ring B, R¹, R², R³, R⁴,R⁵, R⁶, m, n, q, and r is as defined above and described in embodiments,classes and subclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula II,

or a pharmaceutically acceptable salt thereof, wherein each of X, A,ring B, R¹, R⁶, m, n, and q is as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination.

In certain embodiments, the present invention provides a compound offormula III,

or a pharmaceutically acceptable salt thereof, wherein each of A, ringB, R¹, R⁶, and q is as defined above and described in embodiments,classes and subclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula IV,

or a pharmaceutically acceptable salt thereof, wherein each of ring B,R¹, R⁶, and q is as defined above and described in embodiments, classesand subclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula V,

or a pharmaceutically acceptable salt thereof, wherein each of A, ringB, R¹, R⁶, and q is as defined above and described in embodiments,classes and subclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula VI,

or a pharmaceutically acceptable salt thereof, wherein each of A and R¹is as defined above and described in embodiments, classes and subclassesabove and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula VII,

or a pharmaceutically acceptable salt thereof, wherein each of X, A,ring B, R¹, R⁶, m, n, and q is as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination.

In certain embodiments, the present invention provides a compound offormula VIII,

or a pharmaceutically acceptable salt thereof, wherein each of X, A,ring B, R¹, R⁶, m, n, and q is as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination.

In certain embodiments, the invention provides a compound selected from1-111 from the Examples.

In some embodiments, the present invention provides a compound selectedfrom those depicted above, or a pharmaceutically acceptable saltthereof.

Various structural depictions may show a heteroatom without an attachedgroup, radical, charge, or counterion. Those of ordinary skill in theart are aware that such depictions are meant to indicate that theheteroatom is attached to hydrogen

is understood to be

In certain embodiments, the compounds of the invention were synthesizedin accordance with the schemes provided in the Examples below.

4. Uses, Formulation and Administration Pharmaceutically AcceptableCompositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably inhibit or antagonize NaV1.6 in abiological sample or in a patient. In certain embodiments, the amount ofcompound in compositions of this invention is such that is effective tomeasurably inhibit or antagonize NaV1.6 in a biological sample or in apatient. In certain embodiments, a composition of this invention isformulated for administration to a patient in need of such composition.

The term “patient” or “subject”, as used herein, means an animal,preferably a mammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat are used in the compositions of this invention include, but are notlimited to, ion exchangers, alumina, aluminum stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

Compositions of the present invention are administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention include aqueous or oleaginous suspension.These suspensions are formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that are employed are water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium.

For this purpose, any bland fixed oil employed includes synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions also contain a long-chain alcohol diluent or dispersant,such as carboxymethyl cellulose or similar dispersing agents that arecommonly used in the formulation of pharmaceutically acceptable dosageforms including emulsions and suspensions. Other commonly usedsurfactants, such as Tweens, Spans and other emulsifying agents orbioavailability enhancers which are commonly used in the manufacture ofpharmaceutically acceptable solid, liquid, or other dosage forms arealso be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention are orallyadministered in any orally acceptable dosage form. Exemplary oral dosageforms are capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents are optionally also added.

Alternatively, pharmaceutically acceptable compositions of thisinvention are administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention are alsoadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches are also used.

For topical applications, provided pharmaceutically acceptablecompositions are formulated in a suitable ointment containing the activecomponent suspended or dissolved in one or more carriers. Exemplarycarriers for topical administration of compounds of this are mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, provided pharmaceutically acceptable compositions can beformulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Pharmaceutically acceptable compositions of this invention areoptionally administered by nasal aerosol or inhalation. Suchcompositions are prepared according to techniques well-known in the artof pharmaceutical formulation and are prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or otherconventional solubilizing or dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that are optionallycombined with the carrier materials to produce a composition in a singledosage form will vary depending upon the host treated, the particularmode of administration. Preferably, provided compositions should beformulated so that a dosage of between 0.01-100 mg/kg body weight/day ofthe compound can be administered to a patient receiving thesecompositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In certain embodiments, the invention provides a method for inhibitingor antagonizing NaV1.6 in a patient or in a biological sample comprisingthe step of administering to said patient or contacting said biologicalsample with a compound according to the invention.

In certain embodiments, the invention is directed to the use ofcompounds of the invention and/or physiologically acceptable saltsthereof, for modulating or inhibiting/antagonizing NaV1.6. The term“modulation” denotes any change in NaV1.6-mediated signal transduction,which is based on the action of the specific inventive compounds capableto interact with the NaV1.6 target in such a manner that makesrecognition, binding and activating possible. The compounds arecharacterized by such a high affinity to NaV1.6. In certain embodiments,the substances are highly selective for NaV1.6 over most other channelsin order to guarantee an exclusive and directed recognition with thesingle NaV1.6 target. In the context of the present invention, the term“recognition”—without being limited thereto—relates to any type ofinteraction between the specific compounds and the target, particularlycovalent or non-covalent binding or association, such as a covalentbond, hydrophobic/hydrophilic interactions, van der Waals forces, ionpairs, hydrogen bonds, ligand-receptor (enzyme-inhibitor) interactions,and the like. Such association may also encompass the presence of othermolecules such as peptides, proteins or nucleotide sequences. Thepresent ion channel interaction is characterized by high affinity, highselectivity and minimal or even lacking cross-reactivity to other targetmolecules to exclude unhealthy and harmful impacts to the treatedsubject.

In certain embodiments, the present invention relates to a method forinhibiting or antagonizing NaV1.6, with at least one compound of formula(I) according to the invention and/or physiologically acceptable saltsthereof, under conditions such that said NaV1.6 isinhibited/antagonized. In certain embodiments, the system is a cellularsystem. The cellular system is defined to be any subject provided thatthe subject comprises cells. Hence, the cellular system can be selectedfrom the group of single cells, cell cultures, tissues, organs andanimals. In certain embodiments, the method for modulating NaV1.6 isperformed in-vitro. The prior teaching of the present specificationconcerning the compounds of formula (I), including any embodimentsthereof, is valid and applicable without restrictions to the compoundsaccording to formula (I) and their salts when used in the method forinhibiting/antagonizing NaV1.6. The prior teaching of the presentspecification concerning the compounds of formula (I), including anyembodiments thereof, is valid and applicable without restrictions to thecompounds according to formula (I) and their salts when used in themethod for inhibiting/antagonizing NaV1.6.

Provided compounds are inhibitors/antagonists of NaV1.6 and aretherefore useful for treating one or more disorders associated withactivity of NaV1.6. Thus, in some embodiments, the present inventionprovides a method for treating a NaV1.6-mediated disorder comprising thestep of administering to a patient in need thereof a compound of thepresent invention, or pharmaceutically acceptable composition thereof.

In yet another aspect, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migrane, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, myotonia, arrhythmia, movement disorders, neuroendocrinedisorders, ataxia, multiple sclerosis, irritable bowel syndrome,incontinence, visceral pain, osteoarthritis pain, postherpeticneuralgia, diabetic neuropathy, radicular pain, sciatica, back pain,head or neck pain, severe or intractable pain, nociceptive pain,breakthrough pain, postsurgical pain, or cancer pain is providedcomprising administering an effective amount of a compound, or apharmaceutically acceptable composition comprising a compound to asubject in need thereof. In certain embodiments, a method for thetreatment or lessening the severity of acute, chronic, neuropathic, orinflammatory pain is provided comprising administering an effectiveamount of a compound or a pharmaceutically acceptable composition to asubject in need thereof. In certain other embodiments, a method for thetreatment or lessening the severity of radicular pain, sciatica, backpain, head pain, or neck pain is provided comprising administering aneffective amount of a compound or a pharmaceutically acceptablecomposition to a subject in need thereof. In still other embodiments, amethod for the treatment or lessening the severity of severe orintractable pain, acute pain, postsurgical pain, back pain, tinnitis orcancer pain is provided comprising administering an effective amount ofa compound or a pharmaceutically acceptable composition to a subject inneed thereof.

The compounds of the present invention are useful in the prophylaxis andtreatment of autoimmune and/or inflammatory disorders, includingneurodegenerative diseases, such as multiple sclerosis (MS),polyneuritis, multiple neuritis, amyotrophic lateral sclerosis (ALS),Alzheimer's disease or Parkinson's disease.

The present invention furthermore relates to a method of treating asubject suffering from an immunerogulatory abnomality, comprisingadministering to said subject a compound of formula I in an amount thatis effective for treating said immunoregulatory abnormality. The presentinvention preferably relates to a method wherein the immunoregulatoryabnormality is an autoimmune or chronic inflammatory disease selectedfrom the group consisting of: amyotrophic lateral sclerosis (ALS),Alzheimer's disease, Parkinson's disease, systemic lupus erythematosus,chronic rheumatoid arthritis, type I diabetes mellitus, inflammatorybowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn'sdisease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis,autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves'ophthalmopathy and asthma. The present invention furthermore relates toa method wherein the immunoregulatory abnormality is bone marrow ororgan transplant rejection or graft-versus-host disease. The presentinvention furthermore relates to a method wherein the immunoregulatoryabnormality is selected from the group consisting of: transplantation oforgans or tissue, graft-versus-host diseases brought about bytransplantation, autoimmune syndromes including rheumatoid arthritis,systemic lupus erythematosus, Hashimoto's thyroiditis, multiplesclerosis, myasthenia gravis, type I diabetes, uveitis, posterioruveitis, allergic encephalomyelitis, glomerulonephritis, post-infectiousautoimmune diseases including rheumatic fever and post-infectiousglomerulonephritis, inflammatory and hyperproliferative skin diseases,psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis,seborrhoeic dermatitis, lichen planus, pemphigus, bullous pemphigoid,epidermolysis bullosa, urticaria, angioedemas, vasculitis, erythema,cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata,keratoconjunctivitis, vernal conjunctivitis, uveitis associated withBehcet's disease, keratitis, herpetic keratitis, conical cornea,dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, 5Mooren's ulcer, scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Haradasyndrome, sarcoidosis, pollen allergies, reversible obstructive airwaydisease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsicasthma, dust asthma, chronic or inveterate asthma, late asthma andairway hyper-responsiveness, bronchitis, gastric ulcers, vascular damagecaused by ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal burns, coeliac diseases, proctitis,eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerativecolitis, migraine, rhinitis, eczema, interstitial nephritis,Goodpasture's syndrome, hemolytic-uremic syndrome, diabetic nephropathy,multiple myositis, Guillain-Barre syndrome, Meniere's disease,polyneuritis, multiple neuritis, mononeuritis, radiculopathy,hyperthyroidism, Basedow's disease, pure red cell aplasia, aplasticanemia, hypoplastic anemia, idiopathic thrombocytopenic purpura,autoimmune hemolytic anemia, agranulocytosis, pernicious anemia,megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis,fibroid lung, idiopathic interstitial pneumonia, dermatomyositis,leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity,cutaneous T cell lymphoma, chronic lymphocytic leukemia,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia ossea dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy, pyoderma and Sezary'ssyndrome, Addison's disease, ischemiareperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenesis, metastasis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis, sclerosing cholangitis, partial liver resection, 35acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock,or anoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis,alcoholic cirrhosis, hepatic failure, fulminant hepatic failure,late-onset hepatic failure, “acute-on-chronic” liver failure,augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMVinfection, AIDS, cancer, senile dementia, trauma, and chronic bacterialinfection.

In certain embodiments of the present invention an “effective amount” ofthe compound or pharmaceutically acceptable composition is that amounteffective for treating or lessening the severity of a disease ordisorder provide supra.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of adisease or disorder provide supra.

The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. The compounds of the invention are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form”, as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium ion channels. In one embodiment,the compounds and compositions of the invention are inhibitors of one ormore of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8,or NaV1.9, and thus, without wishing to be bound by any particulartheory, the compounds and compositions are particularly useful fortreating or lessening the severity of a disease, condition, or disorderwhere activation or hyperactivity of one or more of NaV1.1, NaV1.2,NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9 is implicatedin the disease, condition, or disorder. When activation or hyperactivityof NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9, is implicated in a particular disease, condition, or disorder,the disease, condition, or disorder may also be referred to as a“NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 orNaV1.9-mediated disease, condition or disorder”. Accordingly, in anotheraspect, the present invention provides a method for treating orlessening the severity of a disease, condition, or disorder whereactivation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3,NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9 is implicated in thedisease state.

In certain embodiments, the compounds and compositions of the inventionare inhibitors of NaV1.6.

The activity of a compound utilized in this invention as an inhibitor ofNaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, orNaV1.9, may be assayed according to methods described generally in theexamples herein, or according to methods available to one of ordinaryskill in the art.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”. For example, exemplary additional therapeutic agentsinclude, but are not limited to: nonopioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such saNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as ASS (Aspirin), Choline magnesium trisalicylate, Diflunisal;fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles suchas Phenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blocade), neurosurgical (neurolysis of CNSpathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, SeventeenthEdition, Ed. Mark H. Beers and Robert Berkow, Merck ResearchLaboratories, 1999, and the Food and Drug Administration website,www.fda.gov, the entire contents of which are hereby incorporated byreference.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. Suitable coatingsand the general preparation of coated implantable devices are describedin U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting NaV1.6 activity ina biological sample or a patient, which method comprises administeringto the patient, or contacting said biological sample with a compound offormula I or a composition comprising said compound. The term“biological sample”, as used herein, includes, without limitation, cellcultures or extracts thereof; biopsied material obtained from a mammalor extracts thereof; and blood, saliva, urine, feces, semen, tears, orother body fluids or extracts thereof.

Inhibition of NaV1.6 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of sodiumion channels in biological and pathological phenomena; and thecomparative evaluation of new sodium ion channel inhibitors.

Compounds of formula (I) and/or a physiologically acceptable saltthereof can furthermore be employed as intermediate for the preparationof further medicament active ingredients. The medicament is preferablyprepared in a non-chemical manner, e.g. by combining the activeingredient with at least one solid, fluid and/or semi-fluid carrier orexcipient, and optionally in conjunction with a single or more otheractive substances in an appropriate dosage form.

The compounds of formula (I) according to the invention can beadministered before or following an onset of disease once or severaltimes acting as therapy. The aforementioned compounds and medicalproducts of the inventive use are particularly used for the therapeutictreatment. A therapeutically relevant effect relieves to some extent oneor more symptoms of a disorder, or returns to normality, eitherpartially or completely, one or more physiological or biochemicalparameters associated with or causative of a disease or pathologicalcondition. Monitoring is considered as a kind of treatment provided thatthe compounds are administered in distinct intervals, e.g. in order toboost the response and eradicate the pathogens and/or symptoms of thedisease completely. Either the identical compound or different compoundscan be applied. The methods of the invention can also be used to reducethe likelihood of developing a disorder or even prevent the initiationof disorders associated with Nav1.6 activity in advance or to treat thearising and continuing symptoms.

In the meaning of the invention, prophylactic treatment is advisable ifthe subject possesses any preconditions for the aforementionedphysiological or pathological conditions, such as a familialdisposition, a genetic defect, or a previously incurred disease.

The invention furthermore relates to a medicament comprising at leastone compound according to the invention and/or pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios. In certain embodiments, the inventionrelates to a medicament comprising at least one compound according tothe invention and/or physiologically acceptable salts thereof.

A “medicament” in the meaning of the invention is any agent in the fieldof medicine, which comprises one or more compounds of formula (I) orpreparations thereof (e.g. a pharmaceutical composition orpharmaceutical formulation) and can be used in prophylaxis, therapy,follow-up or aftercare of patients who suffer from diseases, which areassociated with Nav1.6 activity, in such a way that a pathogenicmodification of their overall condition or of the condition ofparticular regions of the organism could establish at least temporarily.

In various embodiments, the active ingredient may be administered aloneor in combination with other treatments. A synergistic effect may beachieved by using more than one compound in the pharmaceuticalcomposition, i.e. the compound of formula (I) is combined with at leastanother agent as active ingredient, which is either another compound offormula (I) or a compound of different structural scaffold. The activeingredients can be used either simultaneously or sequentially.

Included herein are methods of treatment in which at least one chemicalentity provided herein is administered in combination with ananti-inflammatory agent. Anti-inflammatory agents include but are notlimited to NSAIDs, non-specific and COX-2 specific cyclooxygenase enzymeinhibitors, gold compounds, corticosteroids, methotrexate, tumornecrosis factor (TNF) antagonists, immunosuppressants and methotrexate.

Examples of NSAIDs include, but are not limited to, ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors such as celecoxib, valdecoxib, lumiracoxib and/or etoricoxib.

In some embodiments, the anti-inflammatory agent is a salicylate.Salicylates include by are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be cortisone, dexamethasone, methylprednisolone,prednisolone, prednisolone sodium phosphate, or prednisone.

In additional embodiments the anti-inflammatory agent is a gold compoundsuch as gold sodium thiomalate or auranofin.

The invention also includes embodiments in which the anti-inflammatoryagent is a metabolic inhibitor such as a dihydrofolate reductaseinhibitor, such as methotrexate or a dihydroorotate dehydrogenaseinhibitor, such as leflunomide.

Other embodiments of the invention pertain to combinations in which atleast one anti-inflammatory compound is an anti-monoclonal antibody(such as eculizumab or pexelizumab), a TNF antagonist, such asentanercept, or infliximab, which is an anti-TNF alpha monoclonalantibody.

Still other embodiments of the invention pertain to combinations inwhich at least one active agent is an immunosuppressant compound such asan immunosuppressant compound chosen from methotrexate, leflunomide,cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined above may be applied as a monotherapyor may involve, in addition to the herein disclosed compounds of formulaI, conventional surgery or radiotherapy or medicinal therapy. Suchmedicinal therapy, e.g. a chemotherapy or a targeted therapy, mayinclude one or more, but preferably one, of the following anti-tumoragents:

Alkylating agents: such as altretamine, bendamustine, busulfan,carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine,ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol,mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan,mechloretamine, carboquone; apaziquone, fotemustine, glufosfamide,palifosfamide, pipobroman, trofosfamide, uramustine, TH-302⁴, VAL-083⁴;Platinum Compounds: such as carboplatin, cisplatin, eptaplatin,miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin,satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;DNA altering agents: such as amrubicin, bisantrene, decitabine,mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine,brostallicin, pixantrone, laromustine^(1,3);Topoisomerase Inhibitors: such as etoposide, irinotecan, razoxane,sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptiniumacetate, voreloxin;Microtubule modifiers: such as cabazitaxel, docetaxel, eribulin,ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine,vindesine, vinflunine; fosbretabulin, tesetaxel;Antimetabolites: such as asparaginase³, azacitidine, calciumlevofolinate, capecitabine, cladribine, cytarabine, enocitabine,floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine,methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine,thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed,sapacitabine, tegafur^(2,3), trimetrexate;Anticancer antibiotics: such as bleomycin, dactinomycin, doxorubicin,epirubicin, idarubicin, levamisole, miltefosine, mitomycin C,romidepsin, streptozocin, valrubicin, zinostatin, zorubicin,daunurobicin, plicamycin; aclarubicin, peplomycin, pirarubicin;Hormones/Antagonists: such as abarelix, abiraterone, bicalutamide,buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone,estradiol, fluocortolone fluoxymesterone, flutamide, fulvestrant,goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin,nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen,thyrotropin alfa, toremifene, trilostane, triptorelin,diethylstilbestrol; acolbifene, danazol, deslorelin, epitiostanol,orteronel, enzalutamide^(1,3);Aromatase inhibitors: such as aminoglutethimide, anastrozole,exemestane, fadrozole, letrozole, testolactone; formestane;Small molecule kinase inhibitors: such as crizotinib, dasatinib,erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib,ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib,gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib,dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib,linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib,perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib,tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib,apatinib⁴, cabozantinib S-malate^(1,3), ibrutinib^(1,3), icotinib⁴,buparlisib², cipatinib⁴, cobimetinib^(1,3), idelalisib^(1,3),fedratinib¹, XL-647⁴;Photosensitizers: such as methoxsalen³; porfimer sodium, talaporfin,temoporfin;Antibodies: such as alemtuzumab, besilesomab, brentuximab vedotin,cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab,tositumomab, trastuzumab, bevacizumab, pertuzumab^(2,3); catumaxomab,elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab,nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab,rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab,matuzumab, dalotuzumab^(1,2,3), onartuzumab^(1,3), racotumomab¹,tabalumab^(1,3), EMD-525797⁴, nivolumab^(1,3);Cytokines: such as aldesleukin, interferon alfa², interferon alfa2a³,interferon alfa2b^(2,3); celmoleukin, tasonermin, teceleukin,oprelvekin^(1,3), recombinant interferon beta-1a⁴;Drug Conjugates: such as denileukin diftitox, ibritumomab tiuxetan,iobenguane I123, prednimustine, trastuzumab emtansine, estramustine,gemtuzumab, ozogamicin, aflibercept; cintredekin besudotox, edotreotide,inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox,technetium (99mTc) arcitumomab^(1,3), vintafolide^(1,3);Vaccines: such as sipuleucel³; vitespen³, emepepimut-S³, oncoVAX⁴,rindopepimut³, troVax⁴, MGN-1601⁴, MGN-1703⁴; andMiscellaneous: alitretinoin, bexarotene, bortezomib, everolimus,ibandronic acid, imiquimod, lenalidomide, lentinan, metirosine,mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel³,sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin,vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide,entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib,lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin,pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat,thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar,gendicine⁴, picibanil⁴, reolysin⁴, retaspimycin hydrochloride^(1,3),trebananib^(2,3), virulizin⁴, carfilzomib^(1,3), endostatin⁴,immucothel⁴, belinostat³, MGN-1703⁴.(¹Prop. INN (Proposed International Nonproprietary Name); ² Rec. INN(Recommended International Nonproprietary Names); ³ USAN (United StatesAdopted Name); ⁴ no INN).

In another aspect, the invention provides for a kit consisting ofseparate packs of an effective amount of a compound according to theinvention and/or pharmaceutically acceptable salts, derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally, an effective amount of a further activeingredient. The kit comprises suitable containers, such as boxes,individual bottles, bags or ampoules. The kit may, for example, compriseseparate ampoules, each containing an effective amount of a compoundaccording to the invention and/or pharmaceutically acceptable salts,derivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and an effective amount of a further activeingredient in dissolved or lyophilized form.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment is administered afterone or more symptoms have developed. In other embodiments, treatment isadministered in the absence of symptoms. For example, treatment isadministered to a susceptible individual prior to the onset of symptoms(e.g., in light of a history of symptoms and/or in light of genetic orother susceptibility factors). Treatment is also continued aftersymptoms have resolved, for example to prevent or delay theirrecurrence.

The compounds and compositions, according to the method of the presentinvention, are administered using any amount and any route ofadministration effective for treating or lessening the severity of adisorder provided above. The exact amount required will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, itsmode of administration, and the like. Compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention are administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 100mg/kg and preferably from about 1 mg/kg to about 50 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms optionally contain inert diluents commonly usedin the art such as, for example, water or other solvents, solubilizingagents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions are formulated according to the known art usingsuitable dispersing or wetting agents and suspending agents. The sterileinjectable preparation are also a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This is accomplished by the useof a liquid suspension of crystalline or amorphous material with poorwater solubility. The rate of absorption of the compound then dependsupon its rate of dissolution that, in turn, may depend upon crystal sizeand crystalline form. Alternatively, delayed absorption of aparenterally administered compound form is accomplished by dissolving orsuspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar—agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form also optionally comprises buffering agents.

Solid compositions of a similar type are also employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype are also employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms optionally also comprisebuffering agents. They optionally contain opacifying agents and can alsobe of a composition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as required. Ophthalmicformulation, ear drops, and eye drops are also contemplated as beingwithin the scope of this invention. Additionally, the present inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms can be made by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting Nav1.6 activity in a biological sample comprising the step ofcontacting said biological sample with a compound of this invention, ora composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting Nav1.6 activity in a biological sample in a positive manner,comprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound.

The compounds of the invention can be applied either themselves and/orin combination with physical measurements for diagnostics of treatmenteffectiveness. Pharmaceutical compositions containing said compounds andthe use of said compounds to treat Nav1.6-mediated conditions is apromising, novel approach for a broad spectrum of therapies causing adirect and immediate improvement in the state of health, whether inhuman or animal. The orally bioavailable and active new chemicalentities of the invention improve convenience for patients andcompliance for physicians.

The compounds of formula (I), their salts, isomers, tautomers,enantiomeric forms, diastereomers, racemates, derivatives, prodrugsand/or metabolites are characterized by a high specificity andstability, low manufacturing costs and convenient handling. Thesefeatures form the basis for a reproducible action, wherein the lack ofcross-reactivity is included, and for a reliable and safe interactionwith the target structure.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

The symbols and conventions used in the following descriptions ofprocesses, schemes, and examples are consistent with those used in thecontemporary scientific literature, for example, the Journal of theAmerican Chemical Society or the Journal of Biological Chemistry.

Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Centigrade). All reactions were conducted at room temperatureunless otherwise noted. All compounds of the present invention weresynthesized by processes developed by the inventors.

¹H-NMR spectra were recorded on a Bruker Avance III 400 MHz. Chemicalshifts are expressed in parts per million (ppm, δ units). Couplingconstants are in units of Hertz (Hz). Splitting patterns describeapparent multiplicities and are designated as s (singlet), d (doublet),t (triplet), q (quartet), m (multiplet), or br (broad).

Mass spectra were obtained on Agilent 1200 Series mass spectrometersfrom Agilent technologies, using either Atmospheric Chemical Ionization(APCI) or Electrospray Ionization (ESI). Column: XBridge C8, 3.5 μm,4.6×50 mm; Solvent A: water+0.1% TFA; Solvent B: CAN; Flow: 2 ml/min;Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10min 5% B.

HPLC data were obtained using Agilent 1100 series HPLC from Agilenttechnologies using XBridge column (C8, 3.5 μm, 4.6×50 mm). Solvent A:water+0.1% TFA; Solvent B: ACN; Flow: 2 ml/min; Gradient: 0 min: 5% B, 8min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min 5% B.

The microwave reactions were conducted using Biotage Initiator MicrowaveSynthesizer using standard protocols that are known in the art.

Some abbreviations that may appear in this application are as follows:

δ chemical shift d deuterium or doublet dd doublet of doublets DCMdichloromethane DMF dimethylformamide DMSO dimethylsulfoxide THFtetrhydrofuran eq. equivalent h hour ¹H proton HPLC high pressure liquidchromatography J coupling constant LC liquid chromatography m multipletM molecular ion MHz Megahertz min minute mL milliliter MS massspectrometry m/z mass-to-charge ratio NMR nuclear magnetic resonance RBFRound Bottom Flask RT room temperature s singlet TLC thin layerchromatography UV ultraviolet

Compound numbers utilized in the Examples below correspond to compoundnumbers set forth supra.

EXAMPLES Synthetic Intermediates Intermediate 1:3-[(Pyridin-2-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylic acidtert-butyl ester

Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (2.50 g; 11.61mmol; 1.00 eq.) was dissolved in DCM (25.00 ml; 10.00 V), and3-Pyridin-2-yl-methylamine (1.26 g; 11.61 mmol; 1.00 eq.) andtriethylamine (4.52 ml; 34.84 mmol; 3.00 eq.) were added. The reactionmixture was cooled to 0° C. and to it was added2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (5.54g; 17.42 mmol; 1.50 eq.). The reaction mixture was stirred for 12 h atroom temperature and then quenched with ice-water. The organic layer wasconcentrated under reduced pressure to provide the crude product. Theproduct was purified by silica gel column chromatography to provide3-[(Pyridin-2-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylic acidtert-butyl ester (3.40 g; 10.91 mmol; 93.9%; brown gum). ¹H NMR (CDCl₃)δ 8.55 (d, J=4.56 Hz, 1H), 7.71 (t, J=7.60 Hz, 1H), 7.30-7.23 (m, 2H),7.03-7.01 (m, 1H), 4.59 (d, J=4.76 Hz, 2H), 3.64-3.50 (m, 3H), 3.37-3.33(m, 1H), 3.00-2.98 (m, 1H), 2.17-2.12 (m, 2H), 1.46 (s, 9H).

Intermediate 2: Pyrrolidine-3-carboxylic acid (pyridin-2-ylmethyl)-amidehydrochloride

The N-protected amide3-[(Pyridin-2-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylic acidtert-butyl ester (Intermediate 1, 3.40 g; 10.91 mmol; 1.00 eq.) wasstirred with 4M HCl dioxane (10.00 ml; 40.00 mmol; 3.67 eq.) at 0° C.for 3 h. The reaction mixture was concentrated under reduced pressureand purified by recrystallization using dichloromethane-diethylether toafford Pyrrolidine-3-carboxylic acid (pyridin-2-ylmethyl)-amidehydrochloride (2.60 g; 10.54 mmol; 96.6%; off-white solid). ¹H NMR(DMSO-d₆) δ 9.29 (br s, 1H), 9.07-9.04 (m, 2H), 8.69 (d, J=4.32 Hz, 1H),8.21 (t, J=7.88 Hz, 1H), 7.67 (d, J=7.32 Hz, 2H), 4.55 (d, J=5.68 Hz,2H), 3.37-3.34 (m, 1H), 3.28-3.14 (m, 4H), 2.23-2.14 (m, 1H), 2.02-1.94(m, 1H).

Intermediate 3:3-Fluoro-3-[(pyridin-2-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

3-Fluoro-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (Enamine,0.10 g; 0.41 mmol; 1.00 eq.) was dissolved in DCM (2.00 ml; 20.00 V),and to it was added 3-Pyridin-2-yl-methylamine (0.04 g; 0.41 mmol; 1.00eq.) and triethylamine (0.16 ml; 1.22 mmol; 3.00 eq.). The reactionmixture was cooled to 0° C. and2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (0.39g; 0.61 mmol; 1.50 eq.) was added. The reaction mixture was stirred for12 h at room temperature and quenched with ice-water. The organic layerwas concentrated under reduced pressure to provide crude product, whichwas purified by Silica gel column chromatography to provide3-Fluoro-3-[(pyridin-2-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylicacid tert-butyl ester (0.13 g; 0.40 mmol; 97.6%; off-white gum). ¹H NMR(CDCl₃) δ 8.59 (d, J=4.72 Hz, 1H), 7.92 (br s, 1H), 7.79-7.75 (m, 1H),7.35-7.29 (m, 2H), 4.65 (d, J=4.68 Hz, 2H), 4.14-3.66 (m, 3H), 3.58-3.51(m, 1H), 2.60-2.47 (m, 1H), 2.29-2.18 (m, 1H), 1.48 (s, 9H).

Intermediate 4: 3-Fluoro-pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide dihydrochloride

3-Fluoro-3-[(pyridin-2-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylicacid tert-butyl ester (Intermediate 3, 130.00 mg; 0.39 mmol; 1.00 eq.)was stirred with 4M HCl n dioxane (1.00 ml; 4.00 mmol; 10.15 eq.) at 0°C. for 3 h. The reaction mixture was concentrated under reduced pressureand purified by recrystallization using dichloromethane-diethylether toafford 3-Fluoro-pyrrolidine-3-carboxylic acid (pyridin-2-ylmethyl)-amidedihydrochloride (90.00 mg; 0.30 mmol; 76.4%; off-white solid). ¹H NMR(DMSO-d₆) δ 10.02 (br s, 2H), 9.37 (br s, 1H), 8.74-8.73 (m, 1H), 8.30(t, J=7.72 Hz, 1H), 7.74 (d, J=7.68 Hz, 2H), 4.73-4.62 (m, 2H),3.75-3.56 (m, 2H), 3.54-3.29 (m, 3H), 2.50-2.36 (m, 2H).

Intermediate 5:3-Methyl-3-[(pyridin-2-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

3-Methyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (Enamine,2.50 g; 10.58 mmol; 1.00 eq.) was dissolved in DCM (25.00 ml; 10.00 V),and 3-Pyridin-2-yl-methylamine (1.17 g; 10.58 mmol; 1.00 eq.) andtriethylamine (4.12 ml; 31.73 mmol; 3.00 eq.) were added. The reactionmixture was cooled to 0° C. and2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (10.10g; 15.87 mmol; 1.50 eq.) was added. The reaction mixture was stirred for12 h at room temperature and then quenched with ice-water. The organiclayer was concentrated under reduced pressure to give crude product,which was purified by silica gel column chromatography to provide3-Methyl-3-[(pyridin-2-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylicacid tert-butyl ester (3.30 g; 10.27 mmol; 97.1%; Off white gum) ¹H NMR(CDCl₃) δ 8.53 (d, J=4.56 Hz, 1H), 7.70-7.60 (m, 1H), 7.26-7.22 (m, 2H),4.56 (d, J=4.64 Hz, 2H), 3.73 (d, J=10.96 Hz, 1H), 3.53-3.43 (m, 2H),3.36-3.24 (m, 1H), 2.36-2.29 (m, 1H), 1.83-1.80 (m, 1H), 1.46 (s, 9H),1.39 (s, 3H).

Intermediate 6: Methyl-pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide dihydrochloride

The N-protected amide3-Methyl-3-[(pyridin-2-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylicacid tert-butyl ester (Intermediate 5, 3.40 g; 10.54 mmol; 1.00 eq.) wasstirred with 4M HCl in dioxane (15.00 ml; 60.00 mmol; 5.69 eq.) at 0° C.for 3 h. The reaction mixture was concentrated under reduced pressureand purified by recrystallization using dichloromethane-diethylether toafford 3-Methyl-pyrrolidine-3-carboxylic acid (pyridin-2-ylmethyl)-amidedihydrochloride (3.00 g; 10.49 mmol; 99.6%). ¹H NMR (DMSO-d₆) δ 9.60 (brs, 1H), 9.29 (br s, 1H), 9.03 (t, J=5.48 Hz, 1H), 8.75 (d, J=4.96 Hz,1H), 8.36 (t, J=7.52 Hz, 1H), 7.80-7.76 (m, 2H), 4.61 (d, J=5.60 Hz,2H), 3.60-3.56 (m, 1H), 3.28-3.23 (m, 1H), 3.15-3.09 (m, 1H), 2.99-2.93(m, 1H), 2.37-2.30 (m, 1H), 1.90-1.83 (m, 1H), 1.40 (s, 3H).

Intermediate 7: 3-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butylester

3-Formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 15.0 mmol)was taken in methanol (50 mL) and sodium borohydride (0.8 g, 22.5 mmol)was added in portions at room temperature and stirred for 1 h. Thereaction mixture was concentrated under reduced pressure and theresulting residue was purified by column chromatography (pet ether/ethylacetate 20%) to provide the titled compound (66%, 2 g, colorlessliquid). ¹H NMR (DMSO-d₆): δ 4.63-4.64 (m, 1H), 3.20-3.37 (m, 4H),2.92-3.18 (m, 2H), 2.19-2.50 (m, 1H), 1.50-1.98 (m, 2H), 1.38 (s, 9H).

Intermediate 8: 3-Methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acidtert-butyl ester

3-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester(Intermediate 7, 1.5 g, 7.95 mmol) was taken in dry DCM (20 mL) alongwith DIPEA (3.9 mL, 22.3 mmol) and mesyl chloride (0.63 mL, 0.82 mmol)was added to it dropwise and stirred for 2 h at room temperature. Theorganic layer was washed with 10% aqueous solution of sodiumbicarbonate, followed by water, and brine. The organic layer was driedover anhydrous sodium sulphate and concentrated under reduced pressureto provide the title compound (72%, 1.6 g, brown oil). ¹H NMR (DMSO-d₆):δ 4.15-4.17 (m, 1H), 3.00-3.25 (m, 5H), 2.49-2.50 (m, 1H), 1.59-1.90 (m,2H), 1.38 (s, 9H), 0.97 (s, 3H).

Intermediate 9: 1-Pyrrolidin-3-ylmethyl-1H-imidazole hydrochloride

Imidazole (0.58 g, 8.60 mmol) was taken in dry DMF (5 mL) and to thiswas added 60% sodium hydride (0.2 g, 8.58 mmol) at 0° C. and stirred atthe same temperature for 1 h.3-Methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butylester (Intermediate 8, 0.8 g, 2.86 mmol) was added and the reaction washeated to 60° C. for 2 h. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure. Ice was added tothe resulting solid, extracted with DCM, and the organic layer wasconcentrated under reduced pressure to provide the crude product whichwas purified by column chromatography (pet ether/ethyl acetate 55%). Thecolorless oil was treated with 4M HCl in dioxane and stirred for 1 h.The reaction mixture was concentrated under reduced pressure to obtainthe title compound. LCMS: 152.0 (M+1), Rt. 1.32 min, 97.6% (max), 96.5%(220 nm).

Intermediate 10: 3-Isobutylsulfanyl-benzoic acid methyl ester

3-Mercapto-benzoic acid methyl ester (0.35 g, 2.08 mmol) was taken indry DMF along with dry potassium carbonate (0.57 g, 4.16 mmol) andisobutyl iodide (0.38 g, 2.08 mmol), and the mixture was heated at 130°C. under microwave for 3 h. The reaction mixture was filtered andconcentrated under reduced pressure to provide the title compound (64%,0.3 g, colorless liquid). ¹H NMR (DMSO-d₆): δ 7.80-7.80 (m, 1H),7.71-7.74 (m, 1H), 7.58-7.60 (m, 1H), 7.43-7.47 (m, 1H), 3.84 (s, 3H),2.90 (d, J=6.76 Hz, 2H), 1.77-1.80 (m, 1H), 0.98 (d, J=6.64 Hz, 6H).

Intermediate 11: (3-Isobutylsulfanyl-phenyl)-methanol

3-Isobutylsulfanyl-benzoic acid methyl ester (Intermediate, 10, 1 g,4.46 mmol) was dissolved in dry THF (15 mL) and to this was added 2Msolution of lithium borohydride (3.3 mL, 6.69 mmol) in THF. The reactionmixture was stirred for 15 h at room temperature and then ice and ethylacetate was added. The organic layer was dried with sodium sulfate,filtered, and concentrated under reduced pressure to provide the crudeproduct. Purification by column chromatography (pet ether/ethyl acetate10%) provided the desired product (80%, 0.7 g, colorless liquid). ¹H NMR(DMSO-d₆): δ 7.07-7.26 (m, 4H), 5.20 (t, J=5.80 Hz, 1H), 4.45 (d, J=5.80Hz, 2H), 2.83 (d, J=6.80 Hz, 2H), 1.74-1.81 (m, 1H), 0.97 (d, J=6.64 Hz,6H).

Intermediate 12: 1-Chloromethyl-3-isobutylsulfanyl-benzene

(3-Isobutylsulfanyl-phenyl)-methanol (Intermediate 11, 0.7 g, 3.57 mmol)was taken in dry DCM (10 mL) and excess of thionyl chloride (6 mL) wasadded to it drop wise at room temperature. The reaction mixture washeated to reflux for 5 h, cooled to room temperature and treated withice and ethyl acetate. The organic layer was washed with 10% aqueoussodium bicarbonate, water, and brine. The organic layer was dried oversodium sulfate, filtered, and concentrated under reduced pressure toprovide the desired product (30%, 0.23 g, colorless liquid).

¹H NMR: (DMSO-d₆): δ 7.20-7.37 (m, 4H), 4.72 (s, 2H), 2.85-2.87 (m, 2H),1.75-1.82 (m, 1H), 0.97 (d, J=6.64 Hz, 6H).

Intermediate 13: 3-(2-Methyl-propane-1-sulfonyl)-benzoic acid methylester

3-Isobutylsulfanyl-benzoic acid methyl ester (0.3 g, 1.33 mmol) wastaken in dry DCM (10 mL) and cooled to 0° C. To this was added m-CPBA(0.46 g, 2.67 mmol) in portions and the reaction was stirred for 12 h atroom temperature. The reaction mixture was washed with saturated sodiumbicarbonate, water, brine, dried over sodium sulfate, filtered, andconcentrated under reduced pressure to provide the crude product.Purification by column chromatography (pet ether/ethyl acetate 30%)provided the desired product (90%, 0.3 g, colorless liquid). ¹H NMR:(DMSO-d₆): δ 8.37-8.38 (m, 1H), 8.26-8.29 (m, 1H), 8.17-8.20 (m, 1H),7.80-7.84 (m, 1H), 3.90 (s, 3H), 3.29 (d, J=6.48 Hz, 2H), 1.98-2.05 (m,1H), 0.96 (d, J=6.72 Hz, 6H).

Intermediate 14: [3-(2-Methyl-propane-1-sulfonyl)-phenyl]-methanol

Intermediate 14 was synthesized as described for Intermediate 11 fromIntermediate 13. ¹H NMR (DMSO-d₆): δ 7.85 (s, 1H), 7.58-7.77 (m, 3H),5.45 (t, J=5.72 Hz, 1H), 4.60 (d, J=7.76 Hz, 2H), 3.18 (d, J=6.44 Hz,2H), 1.98-2.01 (m, 1H), 0.96 (d, J=6.72 Hz, 6H).

Intermediate 15: 1-Chloromethyl-3-(2-methyl-propane-1-sulfonyl)-benzene

Intermediate 15 was synthesized according to the procedure described forIntermediate 12 using Intermediate 14 as the starting material. ¹H NMR(DMSO-d₆): δ 7.98 (s, 1H), 7.86-7.88 (m, 1H), 7.65-7.81 (m, 2H), 4.89(s, 2H), 3.22 (d, J=6.44 Hz, 2H), 1.99-2.02 (m, 1H), 0.96 (d, J=6.72 Hz,6H).

Intermediate 16: 1-Pyrrolidin-3-ylmethyl-1H-[1,2,3]triazolehydrochloride

Intermediate 16 was synthesized as described for Intermediate 9 usingIntermediate 8 and triazole as starting materials. LCMS: 153.2 (M+1),Rt. 0.45 min, 86.6% (max), 65% (220 nm).

Intermediate 20: 2-(Pyrrolidin-3-ylmethoxymethyl)-pyridine hydrochloride

Intermediate 20 was synthesized according to the procedure described forIntermediate 9 from Intermediate 8 and3-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester. LCMS193.3 (M+1), Rt. 2.19 min, 93.5% (max).

Intermediate 21: Pyridine-2-carboxylic acid(pyrrolidin-3-ylmethyl)-amide hydrochloride

T3P (50 wt. % solution in ethyl acetate; 5.15 mL; 16.2 mmol) was addedto a solution of 3-Aminomethyl-pyrrolidine-1-carboxylic acid tert-butylester (1.8 g, 8.94 mmol), pyridine-2-carboxylic acid (1 g; 8.13 mmol)and Et₃N (3.4 mL, 24.3 mmol). The reaction mixture was stirred 2 h atroom temperature followed by the addition of water. The organic layerwas dried over sodium sulfate, filtered, and concentrated under reducedpressure to give crude product. Purification by column chromatography(pet ether/ethyl acetate 15%) provided the protected product. Theproduct was treated with 4M HCl in dioxane and stirred at roomtemperature for 3 h. The reaction mixture was concentrated under reducedpressure to provide the desired product as a white solid. LCMS: 206.2(M+1), Rt. 1.05 min, 94.1% (max), 97.6% (254 nm).

Intermediate 22: 3-Isobutoxy-benzaldehyde

3-hydroxy benzaldehyde (25 g, 0.20 mol) was taken in dry DMF (200 mL)along with dry potassium carbonate (84.8 g, 0.60 mol) and to this wasadded isobutyl iodide (55.3 g, 0.30 mol) and heated at 100° C. for 12 h.The reaction mixture was filtered through Celite, and the resultingfiltrate was concentrated under reduced pressure to give a crude oil.Purification by column chromatography resulted in the desired product(53%, 19 g, colorless oil). ¹H NMR: (DMSO-d₆): δ 9.96 (s, 1H), 7.47-7.52(m, 2H), 7.40 (d, J=1.48 Hz, 1H), 7.25-7.28 (m, 1H), 3.80 (d, J=6.52 Hz,2H), 1.99-2.05 (m, 1H), 0.98 (d, J=6.68 Hz, 6H).

Intermediate 23: 1-(3-Isobutoxy-benzyl)-pyrrolidin-3-ol

Intermediate 23 was synthesized using the procedure as described forExample 1 by using Intermediate 22 (5.1 g, 28.7 mmol) and 3-hydroxypyrrolidine (2.5 g, 29.0 mmol) to give the titled compound as acolorless liquid (69%, 5 g, colorless liquid) LCMS: 250.2 (M+1), Rt.3.03 min, 76.1% (max).

Intermediate 24: Methanesulfonic acid1-(3-isobutoxy-benzyl)-pyrrolidin-3-yl ester

Intermediate 24 was synthesized using the procedure as described forIntermediate 8 by using Intermediate 23 (5.0 g, 20.0 mmol) and mesylchloride (2.5 mL, 31.0 mmol) to give the titled compound as a colourlessliquid (60%, 4.2 g). LCMS: 3.47 (M+1), Rt. 3.47 min, 82.2% (max).

Intermediate 25: 1-(3-Isobutoxy-benzyl)-pyrrolidine-3-carbonitrile

Methanesulfonic acid 1-(3-isobutoxy-benzyl)-pyrrolidin-3-yl ester(Intermediate 24, 4.2 g, 12.84 mmol) was dissolved in dry DMSO (10 mL),KCN (1.7 g, 25.68) was added, and the reaction mixture heated at 80° C.for 4 h. The resulting yellow mixture was cooled and brine (4 mL) andwater (4.5 mL) were added. The mixture was extracted with diethyl ether(50 mL X 3), dried over magnesium sulfate, filtered and concentratedunder reduced pressure. The resulting residue was purified by flashchromatography (diethylether/isohexane) (50/50) to give the titledcompound as a colorless oil (82%, 2.7 g). LCMS: 259.0 (M+1), Rt. 3.41min, 90.6% (max), 89.4 (220 nm).

Intermediate 26:N-Hydroxy-1-(3-isobutoxy-benzyl)-pyrrolidine-3-carboxamidine

A solution of 1-(3-Isobutoxy-benzyl)-pyrrolidine-3-carbonitrile(Intermediate 25, 2.7 g, 10.42 mmol) and hydroxylamine (2.1 mL of a 50percent w/v aq. solution, 31.27 mmol) in EtOH (25 mL) was heated toreflux. After 2 h, the reaction mixture was cooled to room temperatureand concentrated in vacuum to afford the title compound as a colorlessliquid (79%. 2.4 g). LCMS: 292.3 (M+1), Rt. 2.82 min, 92.8% (max), 91.1(220 nm).

Intermediate 27: 3-Azido-1-(3-isobutoxy-benzyl)-pyrrolidine

Sodium azide (1.98 g, 30.58 mmol) was added to a solution ofMethanesulfonic acid 1-(3-isobutoxy-benzyl)-pyrrolidin-3-yl ester(Intermediate 24, 5 g, 15.3 mmol) in dry dimethylformamide (25 mL) andthe resultant suspension heated at 65° C. for 8 h. After cooling to roomtemperature, the reaction mixture was diluted with water and extractedinto diethyl ether. The organic phase was washed two further times withwater, then brine. The organic extracts were dried (MgSO₄), filtered andevaporated in vacuo to give an oil. This was purified by flashchromatography on silica, eluting with diethyl ether/cyclohexane (20:80to 40:60), to give the title compound as an oil (73%, 3.1 g, colorlessliquid) LCMS: 275.1 (M+1), Rt. 3.58 min, 91.7% (max).

Intermediate 28: 1-(3-Isobutoxy-benzyl)-pyrrolidine-3-carboxylic acidmethyl ester

Intermediate 28 was synthesized using the procedure as described forIntermediate 23 by using 3-Isobutoxy-benzaldehyde (Intermediate 22, 3 g,16.9 mmol) and Pyrrolidine-3-carboxylic acid methyl ester (2 g, 15.3mmol) to give the titled compound as a colorless liquid (42%, 1.8 g).LCMS: 292.2 (M+1), Rt. 3.58 min, 95.9% (max).

Intermediate 29: 1-(3-Isobutoxy-benzyl)-pyrrolidine-3-carboxylic acidhydrazide

1-(3-Isobutoxy-benzyl)-pyrrolidine-3-carboxylic acid methyl ester(Intermediate 28, 0.8 g, 2.74 mmol) was taken in ethanol (20 mL) andhydrazine hydrate (5 mL) was added to it. The reaction mixture washeated to reflux for 3 h. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure to give a crude oil.Purification by column chromatography (pet ether/ethyl acetate 25%)provided the titled compound as a colorless oil (75%, 0.6 g). LCMS:292.3 (M+1), Rt. 2.77 min, 88.0% (max), 87.8 (220 nm).

Intermediate 30: Acetic acid2-{N-[1-(3-isobutoxy-benzyl)-pyrrolidine-3-carbonyl]-hydrazino}-2-oxo-ethylester

1-(3-Isobutoxy-benzyl)-pyrrolidine-3-carboxylic acid hydrazide(Intermediate 29, 2 g, 6.87 mmol) was taken in dry DCM (25 mL) alongwith N-methyl morpholine (1.14 mL, 7.56) to which acetoxy acetylchloride (1.4 mL, 10.3 mmol) was added at 0° C. and the reaction mixturewas stirred for 2 h at room temperature. The reaction mixture was washedwith water, then brine and the organic phase was dried over dry sodiumsulphate and purified by column chromatography (pet ether/ethyl acetate15%) to get the titled compound as a colorless oil (53$, 1.4 g). LCMS:392.3 (M+1), Rt. 2.99 min, 71.7% (max).

Intermediate 31: Acetic acid5-[1-(3-isobutoxy-benzyl)-pyrrolidin-3-yl]-[1,3,4]oxadiazol-2-ylmethylester

Acetic acid2-{N′-[1-(3-isobutoxy-benzyl)-pyrrolidine-3-carbonyl]-hydrazino}-2-oxo-ethylester (Intermediate 30, 0.5 g, 1.27 mmol) was taken in dry DCM (10 mL)and triethylamine (0.53 mL, 3.8 mmol) was added to it. The reactionmixture was cooled to 0° C. and 2-chloro-1,3-dimethyl imidazoliniumchloride (0.32 g, 1.91 mmol) was added to it and stirred for 12 h. Thereaction mixture was washed with water, organic phase was dried overanhydrous sodium sulfate, and concentrated under reduced pressure toprovide the crude product, which was purified by column chromatography(pet ether ethyl acetate 35%) to get the titled compound as a colorlessoil (63%, 0.3 g). LCMS: 374.2 (M+1), Rt. 3.26 min, 46.6% (max).

Intermediate 32: methyl 1-(3-phenoxybenzyl)pyrrolidine-3-carboxylate

To a solution of Ethyl pyrrolidine-3-carboxylate (1 equiv),3-Phenoxy-benzaldehyde (1 equiv) and sodiumtriacetoxyborohydride wasmixed in dichloroethane (50 ml) and the mixture was heated at 65° C. for3 h. The reaction mixture was cooled to room temperature, concentratedunder reduced pressure and extracted with ethyl acetate. The combinedorganic layer was washed with water (20 ml) and brine solution, thendried over anhydrous sodium sulfate and evaporated under reducedpressure. The crude residue was purified by column chromatography usingpetroleum ether—ethyl acetate as eluents to provide the pure ester (75%,pale brown gum). ¹H NMR (400 MHz, CD₃OD): δ 7.48 (t, J=7.96 Hz, 1H),7.42-7.38 (m, 2H), 7.29 (d, J=7.64 Hz, 1H), 7.21-7.15 (m, 2H), 7.11-7.08(m, 1H), 7.06-7.06 (m, 2H), 4.40 (d, J=1.72 Hz, 2H), 3.75 (s, 3H), 3.60(br s, 2H), 3.43 (br s, 3H), 2.44 (br s, 1H), 2.33-2.31 (m, 1H).

Intermediate 33: methyl1-(3-(2,2,2-trifluoroethoxy)benzyl)pyrrolidine-3-carboxylate

Intermediate 33 was synthesized as described for Intermediate 32 fromEthyl pyrrolidine-3-carboxylate and 3-trifluoromethoxybenzaldehyde. ¹HNMR (400 MHz, CD₃OD): δ 7.33-7.29 (m, 1H), 7.05-7.03 (m, 2H), 6.96-6.94(m, 1H), 4.60-4.51 (m, 2H), 3.76-3.66 (m, 5H), 3.14-3.10 (m, 1H),2.94-2.89 (m, 1H), 2.85-2.81 (m, 1H), 2.75-2.67 (m, 2H), 2.16-2.10 (m,2H).

Intermediate 34: 1-(3-phenoxybenzyl)pyrrolidine-3-carboxylic acid

To a solution of methyl 1-(3-phenoxybenzyl)pyrrolidine-3-carboxylate(Intermediate 32) in THF (16 mL) and water (4 mL), lithium hydroxide(0.43 g, 0.010 mol) was added and stirred for 12 h at RT. Uponcompletion of reaction, the reaction mixture was concentrated; water wasadded and acidified with 1.5 N HCl to get Pale Brown Gum (80%). ¹H NMR(400 MHz, DMSO-d₆): δ 7.42-7.38 (m, 3H), 7.21-7.19 (m, 1H), 7.17-7.15(m, 1H), 7.13-7.11 (m, 1H), 7.03-7.01 (m, 2H), 6.98-6.96 (m, 1H), 3.97(s, 2H), 3.37-3.03 (m, 4H), 2.89 (s, 2H), 2.11-2.01 (m, 2H).

Intermediate 35:1-(3-(2,2,2-trifluoroethoxy)benzyl)pyrrolidine-3-carboxylic acid

Intermediate 35 was synthesized as described for Intermediate 34 fromIntermediate 33. ¹H NMR (400 MHz, DMSO-d₆): δ 7.26-7.22 (m, 1H),6.96-6.94 (m, 2H), 6.92-6.89 (m, 1H), 4.75-4.69 (m, 2H), 3.58 (s, 2H),2.72-2.62 (m, 2H), 2.55-2.46 (m, 1H), 2.39-2.37 (m, 1H), 1.95-1.91 (m,1H), 1.87-1.84 (m, 1H), 1.77 (s, 2H).

Intermediate 36: 3-Methyl-pyrrolidine-3-carboxylic acid methyl ester

To a solution of 3-methyl-3-pyrrolidine carboxylic acid (1 g, 7.75 mmol)in methanol (15 mL) was added trimethylsilylchloride (4 mL) and thereaction mixture stirred at room temperature under nitrogen for 12 h.The reaction mixture was concentrated under reduced pressure and theresulting residue was purified from column chromatography petether/Ethyl acetate 35%) to afford the titled compound as off whitesolid (88%, 1 g). ¹H NMR: 400 MHz, DMSO-d₆: δ 9.56 (s, 1H), 3.66 (s,3H), 3.45 (d, J=41.52 Hz, 1H), 3.23-3.30 (m, 1H), 3.12-3.19 (m, 1H),3.00 (d, J=11.88 Hz, 1H), 2.23-2.30 (m, 1H), 1.80-1.87 (m, 1H), 1.32 (s,3H). LCMS: 144.0 (M+H), Rt. 1.3 min, 96.7% (max).

Intermediate 37: 3-Methyl-1-(3-phenoxy-benzyl)-pyrrolidine-3-carboxylicacid methyl ester

To a solution of 3-Methyl-pyrrolidine-3-carboxylic acid methyl ester(Intermediate 36, 0.7 g, 4.89 mmol) in dry methanol (10 mL) was added3-phenoxy benzaldehyde (0.96 g, 4.89 mmol) and catalytic amount ofacetic acid (0.5 mL). Then the reaction mixture was stirred for 30 min,cooled to 0° C., sodium cyanoborohydride (0.62 g, 9.79 mmol) was addedand stirred at room temperature under nitrogen for 12 h. The methanolwas completely evaporated under reduced pressure and purified by columnchromatography (pet ether/Ethyl acetate 15%) to offer the titledcompound as colorless liquid (51%, 0.8 g). LCMS: 326.3 (M+H), Rt. 3.6min, 92.3% (max).

Intermediate 38: 3-Methyl-1-(3-phenoxy-benzyl)-pyrrolidine-3-carboxylicacid

To a solution of 3-Methyl-1-(3-phenoxy-benzyl)-pyrrolidine-3-carboxylicacid methyl ester (Intermediate 37, 0.8 g, 2.46 mmol) in methanol (4mL)/THF (4 mL) and water (2 mL) was added lithium hydroxide (0.32 g,7.38 mmol) at 0° C. The reaction mixture was stirred for 3 h at roomtemperature and the methanol/THF was completely evaporated under reducedpressure. The resulting solution was acidified from dilute hydrochloricacid, to offer the titled compound as an off-white solid which wascollected by filtration (65%, 0.5 g). LCMS: 312.3. (M+H), Rt. 3.3 min,86.1% (max).

Intermediate 39: 3-Methyl-1-(3-phenoxy-benzoyl)-pyrrolidine-3-carboxylicacid methyl ester

To a solution of 3-phenoxybenzoic acid (0.15 g, 0.70 mmol) and3-Methyl-pyrrolidine-3-carboxylic acid methyl ester (0.1 g, 0.70 mmol)in dry dichloromethane (10 mL) was added triethylamine (0.29 mL, 2.1mmol). The reaction cooled to 0° C. and T₃P (0.66 mL, 2.1 mmol) wasadded dropwise. The reaction was stirred for 5 h. After the completionof reaction (as evidenced by TLC), the organic layer was washed withwater and purified by column chromatography to offer the titled compoundas colorless liquid (87%, 0.2 g). LCMS: 340.0 (M+H), Rt. 4.6 min, 99.5%(max), 99.5% (254 nm).

Intermediate 40: 3-Methyl-1-(3-phenoxy-benzoyl)-pyrrolidine-3-carboxylicacid

To a solution of 3-Methyl-1-(3-phenoxy-benzoyl)-pyrrolidine-3-carboxylicacid methyl ester (Intermediate 39, 0.2 g, 0.58 mmol) in Methanol (4mL)/THF (4 mL) and water (2 mL) was added lithium hydroxide (0.077 g,1.76 mmol) at 0° C. Then the reaction was stirred for 3 h. After thecompletion of reaction (as evidenced by TLC), the methanol/THF wascompletely evaporated and acidified from dilute hydrochloric acid, tooffer the titled compound as an off-white solid (73%, 0.14 g). ¹HNMR:400 MHz, DMSO-d₆: δ 12.56 (s, 1H), 7.41-7.47 (m, 3H), 7.26-7.39 (m,1H), 7.18-7.24 (m, 1H), 7.04-7.15 (m, 4H), 3.18-3.84 (m, 1H), 3.48-3.52(m, 2H), 3.21 (d, J=10.56 Hz, 1H), 1.90 (s, 1H), 1.79 (t, J=20.76 Hz,1H), 1.19 (s, 3H). LCMS: 326.3 (M+H), Rt. 3.9 min, 98.9% (max), 99.4%(254 nm).

Intermediate 41:3-Methyl-1-(3-trifluoromethoxy-benzyl)-pyrrolidine-3-carboxylic acidmethylester

To a solution of 3-triflurophenoxy benzaldehyde (015 g, 0.78 mmol) indry methanol (10 mL) was added 3-Methyl-pyrrolidine-3-carboxylic acidmethyl ester (0.11 g, 0.78 mmol) and catalytic amount of acetic acid(0.5 mL). The reaction mixture was stirred for 30 min, cooled to 0° C.,sodium cyanoborohydride (0.097 g, 1.7 mmol) was added and stirred at RTunder nitrogen over night. After the completion of reaction (asevidenced by TLC), the methanol was completely evaporated and purifiedby column chromatography to offer the titled compound as colorlessliquid (48%, 0.12 g). LCMS: 318.2 (M+H), Rt. 3.4 min, 33.3% (max).

Intermediate 42:3-Methyl-1-(3-trifluoromethoxy-benzyl)-pyrrolidine-3-carboxylic acid

To a solution of 3-Methyl-1-(3-trifluoromethoxy-benzyl)-pyrrolidine-3carboxylicacidmethylester (Intermediate 41, 0.12 g, 0.37 mmol) inmethanol (4 mL)/THF (4 mL) and water (2 mL) was added lithium hydroxide(0.048 g, 1.13 mmol) at 0° C. The reaction was stirred for 3 h. Afterthe completion of reaction (as evidenced by TLC), the methanol/THF wascompletely evaporated and acidified from dilute hydrochloric acid, tooffer the titled compound as a light brown solid (90%, 0.1 g). LCMS:304.3 (M+H), Rt. 2.9 min, 97.3% (max), ¹H NMR: 400 MHz, DMSO-d6: δ 7.61(m, J=6.80, 3H), 7.42 (s, 1H), 4.26 (s, 2H), 3.33 (s, 2H), 3.11 (s, 2H),1.90 (s, 2H), 1.34 (s, 3H).

Intermediate 43: 3-Cyano-3-hydroxy-pyrrolidine-1-carboxylic acidtert-butyl ester

To a solution of 3-Oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (6g, 32.4 mmol) in H₂O/ether (85 mL/60 mL) was added sodium bisulphate(5.06 g, 48.6 mmol) at 0° C., stirred for 15 min and potassium cyanide(3.16 g, 48.6 mmol) was added and stirred at room temperature overnight.The reaction mixture was diluted with EtOAc and washed with water 4times. The organic layer was dried over anhydrous sodium sulphate andconcentrated under vacuum. The residue was purified by flash columnchromatography (DCM/MeOH::0-3%) to provide the titled compound (52%, 3.6g). LCMS: 13.0 (M+H), Rt. 3.2 min, 99.2% (max).

Intermediate 44: 3-Hydroxy-pyrrolidine-3-carboxylic acid methyl ester

3-Cyano-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester(Intermediate 43, 1 g, 4.72 mmol) was dissolved in 10 mL MeOH andaqueous solution of HCl (1.5 N, 5 mL). The mixture was heated to refluxfor 5 h. The mixture was concentrated under reduced pressure to removewater. The resulting semi-solids were concentrated from 3×20 mLmethanol:toluene (1:1) to remove the residual water. The mixture wasdissolved in 12 mL methanol and 0.4 mL acetyl chloride and stirred for18 h. The solution was concentrated from 2×10 mL methanol and 10 mLmethanol:ethylacetate (1:1) to provide 1.2 g of amber oil. The materialwas used without further purification. LCMS: 146.0 (M+H), Rt. 0.5 min,79.7% (max).

Intermediate 45: 3-Hydroxy-1-(3-phenoxy-benzyl)-pyrrolidine-3-carboxylicacid methyl ester

1-Chloromethyl-3-phenoxy-benzene (Intermediate 47, 1.4 g, 6.42 mmol) wasdissolved in DMF (15 mL). To the reaction mixture added anhydrouspotassium carbonate (6.12 g, 19.26 mmol) and3-Hydroxy-pyrrolidine-3-carboxylic acid methyl ester (Intermediate 44,1.1 g, 7.7 mmol). The reaction mixture was stirred at room temperatureovernight, filtered through celite and, the filtrate was concentratedunder reduced pressure. To the resulting residue was added water andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulphate and concentrated under reducedpressure. Purification by flash column chromatography (DCM/MeOH:0-5%)provided the desired product (69% yield). LCMS: 328.3 (M+H), Rt. 3.2min, 70.2% (max).

Intermediate 46: (3-Phenoxy-phenyl)-methanol

3-phenoxy-benzaldehyde (5 g, 25.22 mmol) was dissolved in dry methanol(60 mL), cooled to 0° C., and sodium borohydride (1.14 g, 30.26 mmol)was added portionwise. The reaction mixture was stirred at roomtemperature for 1.5 h and then concentrated under reduced pressure. Theresulting residue was treated with saturated ammonium chloride solution,extracted with ethyl acetate, dried over anhydrous sodium sulphate, andconcentrated under reduced pressure to provide the desired product (99%,5 g). LCMS: 183.0 (M+H), Rt. 5.4 min, 93.1% (max).

Intermediate 47: 1-Chloromethyl-3-phenoxy-benzene

(3-Phenoxy-phenyl)-methanol (Intermediate 46, 5 g, 25 mmol) wasdissolved in DCM (50 mL), cooled to 0° C., and thionyl chloride (4 ml,50 mmol) was added dropwise followed by a drop of DMF. The reactionmixture was stirred at room temperature for 12 h and concentrated underreduced pressure to remove solvent. To the resulting residue was addedice and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulphate, concentrated under reduced pressure andpurified by column chromatography (95%, 5.2 g). NMR: 400 MHz, DMSO-d₆: δ7.36-7.43 (m, 3H), 7.13-7.20 (m, 2H), 6.95-7.07 (m, 4H), 4.73 (s, 2H).

Intermediate 48: 1-(3-Phenoxy-benzyl)-piperidin-2-one

Sodium hydride (0.97 g, 24.2 mmol) was taken in 100 mL single neckedround bottom flask under nitrogen, cooled to 0° C., and DMF (15 mL) wasadded. Δ-Velerolactum (1.6 g, 16.1 mmol) and1-Chloromethyl-3-phenoxy-benzene (Intermediate 47, 4.58 g, 21 mmol) wereadded dropwise. The reaction mixture was stirred at room temperature for2 h, ice was added, and then concentrated under reduced pressure. Theresulting residue was treated with water and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulphate,concentrated under reduced pressure and purified by flash columnchromatography (DCM/MeOH: 0-5%) to provide the desired product (62%,2.85 g). LCMS: 282.3 (M+H), Rt. 4.5 min, 92.3% (max).

Intermediate 49: 2-Oxo-1-(3-phenoxy-benzyl)-piperidine-3-carboxylic acidethyl ester

1-(3-Phenoxy-benzyl)-piperidin-2-one (Intermediate 48, 2.83 g, 10.07mmol) was taken in THF (30 mL), cooled to −78° C., and 1M THF solutionof lithium bis(trimethyl silyl)amide solution (20 mL, 20.14 mmol) wasadded drop wise. The reaction mixture was stirred for 1 h followed bydropwise addition of ethylchloroformate (0.96 ml, 10.07 mmol) at −78° C.The reaction mixture was stirred at room temperature for 1 h followed byaddition of ice and ethyl acetate. The organic layer was washed withbrine, dried over sodium sulfate, filtered, and concentrated underreduced pressure. Purification by flash column chromatography (0-3%DCM/MeOH) provided the desired product (80%, 2.86 g). LCMS: 354.3 (M+H),Rt. 4.9 min, 89.2% (max).

Intermediate 50:3-Methyl-2-oxo-1-(3-phenoxy-benzyl)-piperidine-3-carboxylic acid ethylester

2-Oxo-1-(3-phenoxy-benzyl)-piperidine-3-carboxylic acid ethyl ester(Intermediate 49, 1.4 g, 3.96 mmol) was taken in THF (15 mL), cooled to−78° C. and then lithium bis(trimethyl silyl)amide solution (1M in THF)(4.75 mL, 4.75 mmol) was added dropwise, followed by methyl iodide (0.8ml, 11.89 mmol). The reaction mixture was stirred at room temperaturefor 12 h and then treated with ice followed by extraction with ethylacetate. The organic layer was dried over anhydrous sodium sulfate,concentrated under reduced pressure and purified by flash columnchromatography (0-3% DCM/MeOH) to give the product (97%, 1.4 g). LCMS:368.3 (M+H), Rt. 5.2 min, 90.9% (max).

Intermediate 51:3-Methyl-2-oxo-1-(3-phenoxy-benzyl)-piperidine-3-carboxylic acid

3-Methyl-2-oxo-1-(3-phenoxy-benzyl)-piperidine-3-carboxylic acid ethylester (Intermediate 50, 1.4 g, 3.81 mmol) was taken in a mixture oftetrahydrofuran (14 mL), methanol (6 mL) and water (2 mL). To this wasadded lithium hydroxide monohydrate (0.489 g, 11.44 mmol) and stirred atroom temperature for 3 h. The reaction mixture was concentrated underreduced pressure and water (20 mL) was added. The aqueous phase wasacidified with aqueous solution of HCl (1.5N) until pH 6 and extractedwith DCM. The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give a solid (93%, 1.2 g). LCMS:296.2 (M+H), Rt. 4.5 min, 94.3% (max).

Intermediate 52:1-(3-Phenoxy-cyclohexa-2,4-dienylmethyl)-pyrrolidin-2-one

To a solution of sodium hydride (0.4 g, 17.5 mmol) in 2 mL of anhydrousDMF was added 2-pyrrolidinone (1 g, 11.7 mmol) in DMF (1 mL) dropwise at0° C. and stirred for 10 min at the same temperature. Then1-bromomethyl-3-phenoxy benzene (2.8 g, 16.6 mmol) was added slowly andstirred for 12 h. The reaction mixture was quenched with ice and thesolid obtained was collected by filtration to provide the titledcompound as a colorless oil (51%, 1.6 g). LCMS: 268.0 (M+H), Rt. 4.3min, 94.1% (max), 94.9 (254 nm).

Intermediate 53: 2-Oxo-1-(3-phenoxy-benzyl)-pyrrolidine-3-carboxylicacid ethyl ester

1-(3-Phenoxy-cyclohexa-2,4-dienylmethyl)-pyrrolidin-2-one (Intermediate52, 4 g, 14.9 mmol) was taken in anhydrous tetrahydrofuran (30 ml) andcooled to −78° C. Lithium bis(trimethylsilyl)amide (16 ml, 16.39 mmol)(IM in THF) was added dropwise to the above solution and stirred for 1 hat the same temperature. Ethylchloroacetate (1.6 g, 14.9 mmol) was addeddropwise and stirred for 2 h. The reaction mixture was quenched with iceand extracted with ethyl acetate. The organic layer was washed withwater then brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to provide the crude product, which was purifiedby column chromatography (pet ether/ethyl acetate 20%) to get the titledcompound as a colorless oil (62%, 3.1 g). LCMS: 340.0 (M+H), Rt. 4.8min, 90.7% (max).

Intermediate 54 and 55:3-Hydroxy-2-oxo-1-(3-phenoxy-benzyl)-pyrrolidine-3-carboxylic acid ethylester and 3-Chloro-2-oxo-1-(3-phenoxy-benzyl)-pyrrolidine-3-carboxylicacid ethyl ester

2-Oxo-1-(3-phenoxy-benzyl)-pyrrolidine-3-carboxylic acid ethyl ester(Intermediate 53, 1.5 g, 4.4 mmol) was taken in 2-propanol (10 mL) andcerium chloride heptahydrate (0.6 g, 1.7 mmol) at room temperature.Oxygen gas was bubbled through the solution for 1 h and then thereaction mixture was stirred under oxygen atmosphere for 12 h. Thereaction mixture was concentrated under reduced pressure and purified bycolumn chromatography (pet ether/ethyl acetate 30%) to obtain the twotitled compounds (Intermediate 54, 78%, 610 mg and Intermediate 55, 51%,520 mg). LCMS: (Intermediate 55) 374.0 (M+H), Rt. 5.17 min, 94.5% (max).LCMS: (Intermediate 54) 356.3 (M+H), Rt. 4.32 min, 77.35% (max).

Intermediate 56:3-Hydroxy-2-oxo-1-(3-phenoxy-benzyl)-pyrrolidine-3-carboxylic acid

3-Hydroxy-2-oxo-1-(3-phenoxy-benzyl)-pyrrolidine-3-carboxylic acid ethylester (Intermediate 54, 0.3 g, 0.84 mmol) was taken in 10 ml oftetrahydrofuran and 10% aqueous solution of sodium hydroxide (5 ml) wasadded to it and stirred for 1 h at room temperature. The reactionmixture was concentrated under reduced pressure and the resultingresidue was acidified with aqueous solution of HCl (1.5N) to pH 3. Thesolid that formed was collected by filtration to give the desiredproduct as a gummy solid (55%, 150 mg). LCMS: 328.2 (M+H), Rt. 3.8 min,82.8% (max).

Intermediate 57:3-Chloro-2-oxo-1-(3-phenoxy-benzyl)-pyrrolidine-3-carboxylic acid

3-Chloro-2-oxo-1-(3-phenoxy-benzyl)-pyrrolidine-3-carboxylic acid ethylester (Intermediate 55, 0.5 g, 1.34 mmol) was taken in 10 mL oftetrahydrofuran and 10% aqueous solution of sodium hydroxide (5 mL) wasadded to it and stirred for 1 h at room temperature. The reactionmixture was concentrated under reduced pressure and acidified withaqueous solution of HCl (1.5N) to pH 3. The solid that formed wascollected by filtration to provide the titled compound as a gummy solid(28%, 130 mg). NMR: 400 MHz, DMSO-d₆: δ 13.91 (s, 1H), 6.87-7.40 (m,9H), 4.38-4.51 (m, 2H), 3.30-3.38 (m, 2H), 2.48-2.50 (m, 1H), 2.31-2.41(m, 1H).

Intermediate 58: 3-(2-Methyl-propane-1-sulfinyl)-benzoic acid methylester

3-Isobutylsulfanyl-benzoic acid methyl ester (0.8 g, 3.57 mmol) wastaken in dry DCM (10 mL) and to this was added chromium (IV) oxide (0.53g, 5.35 mmol) and stirred at room temperature for 12 h. The reactionmixture was concentrated under reduced pressure and the resultingresidue was purified by column chromatography (pet ether/ethyl acetate15%) (58%, 0.5 g, colorless liquid). ¹H NMR: 400 MHz, DMSO-d₆: δ7.92-8.23 (m, 3H), 7.70-7.74 (m, 1H), 3.89 (s, 3H), 2.68-2.80 (m, 2H),2.06-2.09 (m, 1H), 0.97-1.10 (m, 6H).

Intermediate 59: [3-(2-Methyl-propane-1-sulfinyl)-phenyl]-methanol

Intermediate 59 was synthesized using the procedure as described forIntermediate 11 from Intermediate 58 (48%, 0.2 g, colorless liquid).LCMS: 213.0 (M+1), Rt. 2.48 min, 88.9% (max), 87.5% (220 nm).

Intermediate 60: 3-(2-Methyl-propane-1-sulfinyl)-benzaldehyde

[3-(2-Methyl-propane-1-sulfinyl)-phenyl]-methanol (Intermediate 59, 0.2g, 0.70 mmol) was taken in dry DCM (10 mL) and to this was addedDess-Martin periodinane (0.45 g, 1.06 mmol) and stirred at roomtemperature for 12 h. The reaction mixture was washed with 10% aqueoussolution of sodium bicarbonate followed by water and brine, the organiclayer was dried over dry sodium sulfate, concentrated under reducedpressure and purified by column chromatography (pet ether/ethyl acetate15%) to provide the titled product as an oil (68%, 0.1 g). LCMS: 211.0(M+1), Rt. 2.85 min, 80.4% (max), 95.1% (254 nm).

Intermediate 61:3-Methyl-1-(2-phenyl-oxazol-4-ylmethyl)-pyrrolidine-3-carboxylic acid

Intermediate 61 was synthesized according to the procedure forIntermediate 37 from Intermediate 36 and 2-Phenyl-oxazole-4-carbaldehyde(Enamine). ¹H NMR (DMSO-d₆) δ: 7.56-7.25 (m, 3H), 7.21-6.73 (m, 5H),3.83-3.49 (m, 2H), 3.15-2.93 (m, 1H), 2.81-2.29 (m, 5H), 2.19-1.94 (m,1H).

Intermediate 62: 4-(3-Phenoxy-benzyl)-morpholine-2-carboxylic acid ethylester

To a solution of Morpholine-2-carboxylic acid ethyl ester (300.00 mg;1.88 mmol; 1.00 eq.) and 3-Phenoxy-benzaldehyde (0.37 g; 1.88 mmol; 1.00eq.) in DCM (5.00 ml; 78.30 mmol; 41.55 eq.) was added sodiumtriacetoxyborohydride (0.48 g; 2.26 mmol; 1.20 eq.). The reactionmixture was heated to 40° C. for 2 h and then treated with saturatedsodium bicarbonate. The organic layer was dried over sodium sulfate,filtered, and concentrated under reduced pressure to provide a colorlessoil. ¹H NMR (CDCl₃) δ: 7.40-7.26 (m, 3H), 7.16-7.00 (m, 5H), 6.96-6.88(m, 1H), 4.30-4.19 (m, 3H), 4.04 (dt, J=11.1, 3.6 Hz, 1H), 3.76-3.65 (m,1H), 3.53 (q, J=9.0 Hz, 2H), 3.04-2.88 (m, 1H), 2.66-2.55 (m, 1H),2.43-2.26 (m, 2H), 1.30 (t, J=7.5 Hz, 3H).

Intermediate 63: 4-(3-Phenoxy-benzyl)-morpholine-2-carboxylic acid

4-(3-Phenoxy-benzyl)-morpholine-2-carboxylic acid ethyl ester(Intermediate 63, 230.00 mg; 0.61 mmol; 1.00 eq.) was stirred at roomtemperature for 2 h in a solution of KOH (68.03 mg; 1.21 mmol; 2.00 eq.)in MeOH (10.00 ml; 246.57 mmol; 406.66 eq.). The reaction was quenchedby diluting the mixture in DCM and adding 5 mL of HCl (5N). The organiclayer was separated and the aqueous layer was extracted twice by DCM.The combined organic layers were dried over sodium sulfate, filtered,and concentrated under reduced pressure to provide the desired product.¹H NMR (CDCl₃) δ: 7.40-7.26 (m, 3H), 7.16-7.00 (m, 5H), 6.96-6.88 (m,1H), 4.30-4.19 (m, 3H), 4.04 (dt, J=11.1, 3.6 Hz, 1H), 3.76-3.65 (m,1H), 3.04-2.88 (m, 1H), 2.66-2.55 (m, 1H), 2.43-2.26 (m, 2H).

Intermediate 64:3-Methyl-1-(2-phenyl-thiazol-5-ylmethyl)-pyrrolidine-3-carboxylic acid

Intermediate 64 was synthesized as described for Intermediate 61 fromIntermediate 36 and 2-Phenyl-thiazole-5-carbaldehyde. ¹H NMR (300 MHz,DMSO-d₆) δ: 12.25 (br s, 1H), 7.99-7.84 (m, 2H), 7.74 (s, 1H), 7.56-7.40(m, 3H), 3.85 (s, 2H), 2.94 (d, J=9.1 Hz, 1H), 2.63 (dt, J=13.9, 7.3 Hz,2H), 2.39 (d, J=9.1 Hz, 1H), 2.28 (ddd, J=13.3, 7.9, 5.8 Hz, 1H), 1.56(ddd, J=13.5, 8.0, 6.3 Hz, 1H), 1.25 (s, 3H).

Intermediate 65: 3-(Pyrrolidine-1-sulfonyl)-benzoic acid methyl ester

To a solution of 3-(1-pyrrolidinylsulfonyl)benzenecarboxylic acid (500mg; 1.96 mmol; 1.00 eq.) in anhydrous dichloromethane (9 ml) andmethanol (3 ml) was added dropwise a solution of(trimethylsilyl)diazomethane (1.47 ml; 2.94 mmol; 1.50 eq.; 2M inhexanes) and the yellow solution was stirred 4 h at room temperature.The reaction mixture was concentrated under reduced pressure andpurified by column chromatography (hexanes/ethyl acetate 10-40%) to givethe desired product as a white solid (510 mg, 94%). ¹H NMR: (DMSO-d₆): δ8.25 (ddt, J=5.2, 3.3, 1.6 Hz, 2H), 8.09 (ddd, J=7.8, 1.7, 1.3 Hz, 1H),7.81 (t, J=8.0 Hz, 1H), 3.91 (s, 3H), 3.16 (ddd, J=6.8, 4.4, 2.7 Hz,4H), 1.72-1.61 (m, 4H). LCMS: 270 (M+1), Rt. 4.60 min. HPLC: 97.3% (254nm), Rt. 3.82 min.

Intermediate 66: [3-(Pyrrolidine-1-sulfonyl)-phenyl]-methanol

A solution of 3-(pyrrolidine-1-sulfonyl)-benzoic acid methyl ester(intermediate 65; 500 mg; 1.86 mmol; 1.00 eq.) in anhydrous THF (25 ml)was cooled to ° C. A solution of lithium aluminum hydride (1.02 ml; 2.04mmol; 1.10 eq.; 2M in THF) was added dropwise and the colorless solutionwas stirred at 0° C. for 2 h. The colorless solution was poured on 50 mLof ice and neutralized with solid ammonium chloride. The cloudy whiteemulsion was extracted with ethyl acetate, the combined organic phasewashed with brine, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by columnchromatography (hexanes/ethyl acetate 20-80%) to give the desiredproduct as a white solid (385 mg, 86%). ¹H NMR (DMSO-d₆): δ 7.75 (s,1H), 7.66 (dt, J=7.3, 1.7 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.32 (t,J=7.5 Hz, 2H), 5.41 (t, J=5.8 Hz, 1H), 4.60 (d, J=5.8 Hz, 2H), 3.13(ddd, J=6.8, 4.4, 2.7 Hz, 4H), 1.70-1.59 (m, 4H). LCMS: 242 (M+1), Rt.2.86 min. HPLC: 100% (254 nm), Rt. 2.71 min.

Intermediate 67: 3-(Pyrrolidine-1-sulfonyl)-benzaldehyde

A solution of [3-(Pyrrolidine-1-sulfonyl)-phenyl]-methanol (intermediate66; 380 mg; 1.57 mmol; 1.00 eq.) and manganese (iv) oxide (2.74 g; 31.50mmol; 20.00 eq.) in anhhydrous DCM (15 ml) was stirred at roomtemperature for 4 h. The black suspension was filtered on celite andrinsed with DCM. The filtrate was concentrated under reduced pressure.The residue was purified by column chromatography (hexanes/ethyl acetate10-60%) to give the desired product as a white solid (349 mg, 93%). ¹HNMR (DMSO-d₆): δ 10.13 (s, 1H), 8.29 (t, J=1.6 Hz, 1H), 8.20 (dt, J=7.6,1.3 Hz, 1H), 8.15-8.09 (m, 1H), 7.86 (t, J=7.7 Hz, 1H), 3.24-3.13 (m,4H), 1.73-1.59 (m, 4H). LCMS: 240 (M+1), Rt. 3.38 min. HPLC: 100% (254nm), Rt. 3.29 min.

Intermediate 68:1-[3-(Pyrrolidine-1-sulfonyl)-benzyl]-pyrrolidine-3-carboxylic acidmethyl ester

A solution of pyrrolidine-3-carboxylic acid methyl ester hydrochloride(215 mg; 1.30 mmol; 1.00 eq.), 3-(pyrrolidine-1-sulfonyl)-benzaldehyde(intermediate 67; 342 mg; 1.43 mmol; 1.10 eq.) and sodiumtriacetoxyborohydride (386 mg; 1.82 mmol; 1.40 eq.) in anhydrous1,2-dichloroethane (5 ml) was heated at 65° C. for 3 h. The tan cloudysolution was diluted with ethyl acetate, washed with saturated aqueoussodium carbonate and the organic phase was concentrated under reducedpressure. The residue was purified by column chromatography(hexanes/ethyl acetate 20-100%) to give the desired product as acolorless oil (202 mg, 44%). ¹H NMR (DMSO-d₆): δ 7.72 (s, 1H), 7.68 (d,J=7.3 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.59-7.53 (m, 1H), 3.69 (dd,J=35.5, 13.5 Hz, 2H), 3.60 (s, 3H), 3.13 (t, J=6.7 Hz, 4H), 3.04 (ddd,J=14.3, 9.7, 6.5 Hz, 1H), 2.71-2.60 (m, 2H), 2.57-2.51 (m, 2H),2.07-1.89 (m, 2H), 1.70-1.55 (m, 4H). LCMS: 353 (M+1), Rt. 2.31 min.HPLC: 99.3% (254 nm), Rt. 2.44 min.

Example 1 1-(3-p-Tolyloxy-benzyl)-pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide (1)

Pyrrolidine-3-carboxylic acid (pyridin-2-ylmethyl)-amide hydrochloride(Intermediate 2, 75.00 mg; 0.30 mmol; 1.00 eq.), MeOH (1.13 ml; 15.00 V)and triethylamine (0.04 ml; 0.33 mmol; 1.10 eq.) were dissolved inacetic acid (0.04 g; 0.61 mmol; 2.00 eq.), and THF (1.13 ml; 15.00 V)and 3-p-Tolyloxy-benzaldehyde (81.52 mg; 0.36 mmol; 1.20 eq.) wereadded. The reaction mixture was stirred for 2 h at room temperature. Thereaction mixture was cooled to 0° C., sodiumcyanoborohydride (30.17 mg;0.46 mmol; 1.50 eq.) was added and the reaction mixture was stirred for12 h at room temperature. The solvent was removed under reducedpressure, the resulting residue was dissolved in dichloromethane, andwashed with water (2×3 mL), then saturated brine solution. The combinedorganic layer was dried over anhydrous sodium sulphate and evaporatedunder reduced pressure to provide the crude product. Purification firstby silica gel column chromatography to remove the starting materials andthen by DSC-SCX column provided the final compound1-(3-p-Tolyloxy-benzyl)-pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide (38.00 mg; 0.09 mmol; 29.6%; off whitesolid). ¹H NMR (DMSO-d₆) δ 8.47 (d, J=4.28 Hz, 1H), 8.39 (t, J=5.84 Hz,1H), 7.75-7.71 (m, 1H), 7.30-7.17 (m, 4H), 7.04 (d, J=7.72 Hz, 1H),6.91-6.89 (m, 3H), 6.83-6.80 (m, 1H), 4.32 (d, J=5.96 Hz, 2H), 3.53 (s,2H), 2.95-2.85 (m, 1H), 2.80-2.70 (m, 1H), 2.65-2.55 (m, 3H), 2.48-2.41(m, 3H), 2.28 (s, 3H).

The following compounds were synthesized as described for Example 1 fromthe starting materials indicated in the Table.

Starting Cmpd Structure Data Materials 2

  1-[3-(3-Methoxy-phenoxy)-benzyl]- pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (DMSO-d₆) δ 8.47 (d, J = 4.72 Hz. 1H),8.40 (t, J = 5.88 Hz, 1H), 7.74-7.70 (m, 1H), 7.62-7.58 (m, 1H), 7.47(d, J = 8.00 Hz, 1H), 7.37 (t, J = 7.80 Hz, 1H), 7.27-7.15 (m, 5H), 7.05(s, 1H), 6.97-6.95 (m, 1H), 4.32 (d, J = 5.88 Hz, 2H), 3.58 (s, 2H),2.94-2.90 (m, 1H), 2.78 (t, J = 8.60 Hz, 1H), 2.65-2.55 (m, 2H),2.49-2.45 (m, 1H), 1.95-1.91 (m, 2H). Intermediate 2 and 3-(3- Methoxy-phenoxy)- benzaldehyde 3

  1-[3-(3,4-Difluoro-phenoxy)-benzyl]- pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.48-8.46 (m, 1H),7.82-7.77 (m, 1H), 7.36-7.20 (m, 4H), 7.16 (d, J = 7.64 Hz, 1H),7.06-7.05 (m, 1H), 6.95-6.89 (m, 2H), 6.79-6.76 (m, 1H), 4.47 (s, 2H),3.70-3.63 (m, 2H), 3.06-3.01 (m, 1H), 2.94-2.89 (m, 1H), 2.77-2.58 (m,3H), 2.14-2.13 (m, 2H). Intermediate 2 and 3-(3,4- Difluoro- phenoxy)-benzaldehyde 4

  1-[3-(Pyridin-2-yloxy)-benzyl]-pyrrolidine-3- carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.49 (d, J = 4.32 Hz, 1H),8.14-8.13 (m, 1H), 7.88-7.79 (m, 2H), 7.50 (t, J = 7.88 Hz, 1H),7.38-7.28 (m, 4H), 7.19- 7.13 (m, 2H), 7.01 (d, J = 8.32 Hz, 1H),4.54-4.46 (m, 2H), 4.22-4.21 (m, 2H), 3.35-3.27 (m, 5H), 2.38- 2.33 (m,1H), 2.23-2.19 (m, 1H). Intermediate 2 and 3-(Pyridin- 2-yloxy)-benzaldehyde 5

  1-[3-(3-Trifluoromethyl-phenoxy)-benzyl]- pyrrolidine-3-carboxylicacid (pyridin-2-ylmethyl)-amide ¹H NMR (DMSO-d₆) δ 8.47 (d, J = 4.72 Hz,1H), 8.40 (t, J = 5.88 Hz, 1H), 7.74-7.70 (m, 1H), 7.62-7.58 (m, 1H),7.47 (d, J = 8.00 Hz, 1H), 7.37 (t, J = 7.80 Hz, 1H), 7.27-7.15 (m, 5H),7.05 (s, 1H), 6.97-6.95 (m, 1H), 4.32 (d, J = 5.88 Hz, 2H), 3.58 (s,2H), 2.94-2.90 (m, 1H), 2.78 (t, J = 8.60 Hz, 1H), 2.65-2.55 (m, 2H),2.49-2.45 (m, 1H), 1.95-1.91 (m, 2H). Intermediate 2 and 3-(3-Trifluoromethyl- phenoxy)- benzaldehyde 6

  1-[3-(4-Methoxy-phenoxy)-benzyl]- pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.48-8.47 (m, 1H),7.82-7.78 (m, 1H), 7.34-7.24 (m, 3H), 7.03 (d, J = 7.56 Hz, 1H),6.96-6.90 (m, 5H), 6.83-6.81 (m, 1H), 4.47 (s, 2H), 3.79 (s, 3H), 3.66-3.59 (m, 2H), 3.06-3.00 (m, 1H), 2.91 (t, J = 9.32 Hz, 1H), 2.77-2.56(m, 3H), 2.13-2.11 (m, 2H). Intermediate 2 and 3-(4- Methoxy- phenoxy)-benzaldehyde 7

  1-[3-(2-Methoxy-phenoxy)-benzyl]- pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.48 (d, J = 4.68 Hz, 1H),7.82-7.78 (m, 1H), 7.34-7.16 (m, 5H), 7.02-6.93 (m, 3H), 6.89-6.88 (m,1H), 6.77-6.74 (m, 1H), 4.47 (s, 2H), 3.76 (s, 3H), 3.64 (s, 2H),3.06-3.02 (m, 1H), 2.93 (t, J = 9.36 Hz, 1H), 2.77-2.73 (m, 1H),2.69-2.60 (m, 2H), 2.14-2.11 (m, 2H). Intermediate 2 and 3-(2- Methoxy-phenoxy)- benzaldehyde 8

  1-[3-(2,4-Difluoro-phenoxy)-benzyl]- pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.49-8.47 (m, 1H),7.82-7.78 (m, 1H), 7.34-7.27 (m, 3H), 7.18-7.07 (m, 3H), 7.00- 6.96 (m,2H), 6.85-6.82 (m, 1H), 4.47 (s, 2H), 3.68-3.61 (m, 2H), 3.06-3.00 (m,1H), 2.91 (t, J = 9.36 Hz, 1H), 2.76-2.56 (m, 3H), 2.13- 2.05 (m, 2H).Intermediate 2 and 3-(2,4- Difluoro- phenoxy)- benzaldehyde 9

  l-[3-(3,5-Dimethyl-phenoxy)-benzyl]- pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.47 (d, J = 4.64 Hz, 1H),7.81-7.77 (m, 1H), 7.34-7.27 (m, 3H), 7.08 (d, J = 7.56 Hz, 1H), 7.00(s, 1H), 6.88-6.86 (m, 1H), 6.76 (s, 1H), 6.58 (s, 2H), 4.47 (s, 2H),3.66-3.65 (m, 2H), 3.04-3.02 (m, 1H), 2.92 (t, J = 9.24 Hz, 1H),2.75-2.60 (m, 3H), 2.26 (s, 6H), 2.12-2.05 (m, 2H). Intermediate 2 and3-(3,5- Dimethyl- phenoxy)- benzaldehyde 10

  1-[3-(3,4-Dimethyl-phenoxy)-benzyl]- pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.48-8.46 (m, 1H),7.81-7.77 (m, 1H), 7.34-7.25 (m, 3H), 7.10-7.05 (m, 2H), 6.98- 6.97 (m,1H), 6.86-6.83 (m, 1H), 6.78-6.78 (m, 1H), 6.71-6.69 (m, 1H), 4.47 (s,2H), 3.67-3.60 (m, 2H), 3.06-3.02 (m, 1H), 3.00-2.89 (m, 1H), 2.77-2.57(m, 3H), 2.23 (s, 6H), 2.15-2.04 (m, 2H). Intermediate 2 and 3-(3,4-Dimethyl- phenoxy)- benzaldehyde 11

  1-[3-(3-Fluoro-phenoxy)-benzyl]- pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (DMSO-d₆) δ: 8.47 (d, J = 4.64 Hz,1H), 8.40-8.39 (m, 1H), 7.75-7.70 (m, 1H), 7.42-7.33 (m, 2H), 7.25-7.19(m, 2H), 7.14 (d, J = 7.32 Hz, 1H), 7.02 (s, 1H), 6.98-6.93 (m, 2H),6.86-6.83 (m, 2H), 4.32 (d, J = 5.88 Hz, 2H), 3.58 (s, 2H), 2.95- 2.91(m, 1H), 2.79 (t, J = 8.68 Hz, 1H), 2.59-2.43 (m, 3H), 1.95-1.90 (m,2H). Intermediate 2 and 3-(3-Fluoro- phenoxy)- benzaldehyde 12

  1-[3-(Pyridin-3-yloxy)-benzyl]-pyrrolidine-3- carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.80-8.79 (m, 1H),8.63-8.58 (m, 2H), 8.22-8.20 (m, 1H), 8.05 (d, J = 8.00 Hz, 1H),8.02-7.99 (m, 1H), 7.92 (d, J = 8.96 Hz, 1H), 7.63-7.59 (m, 1H), 7.52-7.49 (m, 2H), 7.34 (dd, J = 8.20, 1.24 Hz, 1H), 4.80-4.71 (m, 2H),4.54-4.43 (m, 2H), 3.78-3.45 (m, 4H), 2.78 (s, 3H), 2.62-2.22 (m, 3H).Intermediate 2 and 3-(Pyridin- 3-yloxy)- benzaldehyde 13

  1-[3-(4-Fluoro-phenoxy)-benzyl]-pyrrolidine-3- carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (DMSO-d₆) δ: 11.02 (br s, 1H),9.00-8.90 (m, 1H), 8.63 (b rs, 1H), 8.08 (s, 1H), 7.55-7.45 (m, 3H),7.33-7.24 (m, 4H), 7.11-7.05 (m, 3H), 4.50-4.37 (m, 4H), 3.25-3.14 (m,4H), 2.40-1.90 (m, 3H). Intermediate 2 and 3-(4- Fluorophenoxy)benzylbromide 14

  1-[3-(2-Fluoro-phenoxy)-benzyl]- pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (DMSO-d₆) δ: 8.48-8.47 (m, 1H),8.40-8.38 (m, 1H), 7.75- 7.71 (m, 1H), 7.41-7.13 (m, 7H), 7.06 (d, J =7.48 Hz, 1H), 6.93 (s, 1H), 6.83-6.80 (m, 1H), 4.32 (d, J = 5.92 Hz,2H), 3.55 (s, 2H), 2.94-2.88 (m, 1H), 2.77 (t, J = 8.16 Hz, 1H),2.65-2.55 (m, 1H), 2.35-2.25 (m, 2H), 1.93-1.90 (m, 2H). Intermediate 2and 3-(2-Fluoro- phenoxy)- benzaldehyde 15

  1-(4-Fluoro-3-phenoxy-benzyl)-pyrrolidine-3- carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.80-8.79 (m, 1H),8.63-8.58 (m, 2H), 8.22-8.20 (m, 1H), 8.05 (d, J = 8.00 Hz, 1H),8.02-7.99 (m, 1H), 7.92 (d, J = 8.96 Hz, 1H), 7.63-7.59 (m, 1H), 7.52-7.49 (m, 2H), 7.34 (dd, J = 8.20, 1.24 Hz, 1H), 4.80-4.71 (m, 2H),4.54-4.43 (m, 2H), 3.78-3.45 (m, 4H), 2.78 (s, 3H), 2.62-2.22 (m, 3H).Intermediate 2 and 4-Fluoro-3- phenoxy- benzaldehyde 16

  1-[3-(4-Isopropyl-phenoxy)-benzyl]- pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.80-8.79 (m, 1H),8.63-8.58 (m, 2H), 8.22-8.20 (m, 1H), 8.05 (d, J = 8.00 Hz, 1H),8.02-7.99 (m, 1H), 7.92 (d, J = 8.96 Hz, 1H), 7.63-7.59 (m, 1H), 7.52-7.49 (m, 2H), 7.34 (dd, J = 8.20, 1.24 Hz, 1H), 4.80-4.71 (m, 2H),4.54-4.43 (m, 2H), 3.78-3.45 (m, 4H), 2.78 (s, 3H), 2.62-2.22 (m, 3H).Intermediate 2 and 3-(4- Isopropyl- phenoxy)- benzaldehyde 17

  1-(3-p-Tolyloxy-benzyl)-pyrrolidine-3- carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.80-8.79 (m, 1H),8.63-8.58 (m, 2H), 8.22-8.20 (m, 1H), 8.05 (d, J = 8.00 Hz, 1H),8.02-7.99 (m, 1H), 7.92 (d, J = 8.96 Hz, 1H), 7.63-7.59 (m, 1H), 7.52-7.49 (m, 2H), 7.34 (dd, J = 8.20, 1.24 Hz, 1H), 4.80-4.71 (m, 2H),4.54-4.43 (m, 2H), 3.78-3.45 (m, 4H), 2.78 (s, 3H), 2.62-2.22 (m, 3H).Intermediate 2 and 3-p- Tolyloxy- benzaldehyde 18

  1-[3-(6-Methyl-pyrazin-2-yloxy)-benzyl]- pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.49-8.47 (m, 1H), 8.19 (d,J = 4.76 Hz, 2H), 7.83- 7.78 (m, 1H), 7.48 (t, J = 7.88 Hz, 1H),7.37-7.30 (m, 4H), 7.20 (dd, J = 8.14, 1.60 Hz, 1H), 4.49 (s, 2H),4.12-4.04 (m, 2H), 3.27-3.10 (m, 5H), 2.37 (s, 3H), 2.33-1.97 (m, 2H).Intermediate 2 and 3-(6- Methyl-pyrazin- 2-yloxy)- benzaldehyde 19

  1-[6-(4-Methoxy-phenoxy)-pyridin-2- ylmethyl]-pyrrolidine-3-carboxylicacid (pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.57-8.55 (m, 1H),8.00-7.96 (m, 1H), 7.88- 7.84 (m, 1H), 7.52-7.45 (m, 2H), 7.15 (d, J =7.24 Hz, 1H), 7.08-7.05 (m, 2H), 6.98-6.96 (m, 3H), 4.57 (s, 2H),4.50-4.40 (m, 2H), 3.80 (s, 3H), 3.70-3.60 (m, 2H), 3.32-3.30 (m, 2H),2.70-2.00 (m, 3H). Intermediate 2 and 6-(4- Melhoxy- phenoxy)-pyridine-2- carbaldehyde 20

  1-[6-(4-Fluoro-phenoxy)-pyridin-2-ylmethyl]- pyrrolidine-3-carboxylicacid (pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.48-8.47 (m, 1H),7.83-7.75 (m, 2H), 7.35-7.30 (m, 2H), 7.18 (d, J = 7.20 Hz, 1H),7.15-7.11 (m, 4H), 6.79 (d, J = 8.04 Hz, 1H), 4.48 (s, 2H), 3.75-3.67(m, 2H), 3.07-2.93 (m, 2H), 2.82-2.66 (m, 3H), 2.15-2.01 (m, 2H).Intermediate 2 and 6-(4-Fluoro- phenoxy)- pyridine-2- carbaldehyde 21

  3-Fluoro-1-(3-m-tolyloxy-benzyl)- pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.58-8.56 (m, 1H),8.00-7.98 (m, 1H), 7.55-7.46 (m, 3H), 7.28-7.25 (m, 2H), 7.20- 7.19 (m,1H), 7.11-7.09 (m, 1H), 7.01-6.99 (m, 1H), 6.87 (s, 1H), 6.84-6.81 (m,1H), 4.69-4.59 (m, 2H), 4.50 (s, 2H), 3.99-3.83 (m, 2H), 3.73-3.60 (m,2H), 2.78-2.55 (m, 2H), 2.33 (s, 3H). Intermediate 4 and 3-m- Tolyloxy-benzaldehyde 22

  3-Fluoro-1-(3-p-tolyloxy-benzyl)- pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.49-8.47 (m, 1H),7.83-7.79 (m, 1H), 7.35-7.27 (m, 3H), 7.17-7.15 (m, 2H), 7.08 (d, J =7.68 Hz, 1H), 7.00-6.99 (m, 1H), 6.90-6.85 (m, 3H), 4.54 (s, 2H),3.74-3.64 (m, 2H), 3.14-2.88 (m, 3H), 2.66-2.60 (m, 1H), 2.55-2.46 (m,1H), 2.32 (s, 3H), 2.30-2.15 (m, 1H). Intermediate 4 and 3-p- Tolyloxy-benzaldehyde 23

  3-Fluoro-1-[3-(3-methoxy-phenoxy)- benzyl]-pyrrolidine-3-carboxylicacid (pyridin-2-ylmethyl)-amide ¹H NMR (DMSO-d₆) δ: 8.81-8.81 (m, 1H),8.48-8.47 (m, 1H), 7.76- 7.72 (m, 1H), 7.35-7.19 (m, 4H), 7.09 (d, J =7.56 Hz, 1H), 6.98 (s, 1H), 6.91-6.88 (m, 1H), 6.72-6.69 (m, 1H),6.58-6.54 (m, 2H), 4.39 (d, J = 5.96 Hz, 2H), 3.71 (s, 3H), 3.63- 3.62(m, 2H), 3.00-2.73 (m, 3H), 2.44-2.37 (m, 2H), 2.13-2.02 (m, 1H).Intermediate 4 and 3-(3- Methoxy- phenoxy)- benzaldehyde 24

  1-[3-(3,4-Difluoro-phenoxy)-benzyl]-3- fluoro-pyrrolidine-3-carboxylicacid (pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.49-8.48 (m, 1H),7.81-7.79 (m, 1H), 7.37-7.16 (m, 5H), 7.07 (s, 1H), 6.95-6.92 (m, 3H),4.54 (s, 2H), 3.75-3.66 (m, 2H) 3.11-2.88 (m, 3H), 2.66-2.60 (m, 1H),2.55-2.42 (m, 1H), 2.30-2.17 (m, 1H). Intermediate 4 and 3-(3,4-Difluoro- phenoxy)- benzaldehyde 25

  3-Fluoro-1-[3-(3-trifluoromethyl-phenoxy)-benzyl]-pyrrolidine-3-carboxylic acid (pyridin-2-ylmethyl)-amide ¹H NMR(CD₃OD) δ: 8.49-8.47 (m, 1H), 7.83-7.78 (m, 1H), 7.56-7.52 (m, 1H),7.41-7.29 (m, 4H), 7.24- 7.21 (m, 3H), 7.12-7.11 (m, 1H), 7.00-6.99 (m,1H), 4.54 (s, 2H), 3.77-3.32 (m, 2H), 3.12-2.89 (m, 3H), 2.64-2.60 (m,1H), 2.55-2.42 (m, 1H), 2.28-2.17 (m, 1H). Intermediate 4 and 3-(3-Trifluoromethyl- phenoxy)- benzaldehyde 26

  3-Fluoro-1-[3-(4-isopropyl-phenoxy)- benzyl]-pyrrolidine-3-carboxylicacid (pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.49-8.47 (m, 1H),7.83-7.79 (m, 1H), 7.35-7.21 (m, 5H), 7.08 (d, J = 7.72 Hz, 1H),7.01-7.00 (m, 1H), 6.93-6.87 (m, 3H), 4.54 (s, 2H), 3.73-3.63 (m, 2H),3.11-2.87 (m, 4H), 2.63-2.58 (m, 1H), 2.51-2.43 (m, 1H), 2.27-2.16 (m,1H), 1.25 (d, J = 6.92 Hz, 6H). Intermediate 4 and 3-(4- Isopropyl-phenoxy)- benzaldehyde 27

  3-Methyl-1-[3-(pyrimidin-2-yloxy)- benzyl]-pyrolidine-3-carboxylicacid (pyridin-2-ylmethyl)-amide ¹H NMR (CD₃OD) δ: 8.56 (d, J = 4.84 Hz,2H), 8.47-8.46 (m, 1H), 7.78-7.74 (m, 1H), 7.39-7.35 (m, 1H), 7.29-7.24(m, 4H), 7.19 (t, J = 4.84 Hz, 1H), 7.10-7.07 (m, 1H), 4.50-4.41 (m,2H), 3.77 (s, 2H), 3.22-3.20 (m, 1H), 3.01-2.97 (m, 1H), 2.65-2.63 (m,1H), 2.41-2.28 (m, 2H), 1.83-1.76 (m, 1H), 1.34 (s, 3H). Intermediate 6and 3- (Pyrimidin-2- yloxy)- benzaldehyde 28

  1-[1-(3-Isobutoxy-benzyl)-pyrrolidin-3- ylmethyl]-1H-imidazole ¹H NMR(DMSO-d₆): δ 7.48 (s, 1H), 7.22 (t, J = 8.04 Hz, 1H), 7.06 (s, 1H),6.79-6.89 (m, 4H), 3.88-3.97 (m, 2H), 3.72 (d, J = 6.52 Hz, 2H), 3.54-3.64 (m, 2H), 2.36-2.74 (m, 5H), 1.95-2.13 (m, 2H), 1.49-1.56 (m, 1H),1.03 (d, J = 6.68 Hz, 6H). Intermediate 9 and 3- Isobutoxy- benzaldehyde29

  1-Biphenyl-3-ylmethyl-pyrrolidine-3- carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (DMSO-d₆): δ 8.45-8.46 (m, 1H), 8.39(t, J = 6.00 Hz, 1H), 7.23-7.72 (m, 12H), 4.32 (d, J = 5.88 Hz, 2H),3.64 (s, 2H), 2.63-2.96 (m, 3H), 2.48-2.51 (m, 2H), 1.93-1.96 (m, 2H).Intermediate 1 and 3- biphenylcar- boxaldehyde 30

  1-[3-(2,2,2-Trifluoro-ethoxy)-benzyl]- pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide ¹H NMR (DMSO-d₆): δ 8.46-8.48 (m, 1H),8.38-8.41 (m, 1H), 7.71- 7.75 (m, 1H), 7.19-7.28 (m, 3H), 6.90-6.99 (m,3H), 4.69-4.76 (m, 2H), 4.33 (d, J = 5.88 Hz, 2H), 3.54 (s, 2H),2.40-2.93 (m, 5H), 1.92-1.96 (m, 2H). Intermediate 1 and 3-(2,2,2-Trifluoro- ethoxy)- benzaldehyde 31

  1-(2,2-Difluoro-benzo[1,3]dioxol-5- ylmethyl)-pyrrolidine-3-carboxylicacid (pyridin-2-ylmethyl)-amide ¹H NMR (DMSO-d₆): δ 8.46-8.48 (m, 1H),8.39 (t, J = 5.84 Hz, 1H), 7.71-7.75 (m, 1H), 7.12-7.34 (m, 5H), 4.33(d, J = 5.88 Hz, 2H), 3.57 (s, 2H), 2.39-2.95 (m, 5H), 1.90-1.96 (m,2H). Intermediate 1 and 2,2- Difluoro- benzo[1,3] dioxole-5-carbaldehyde 32

  1-(2,2-Dimethyl-2,3-dihydro- benzofuran-5-ylmethyl)-pyrrolidine-3-carboxylic acid (pyridin-2-ylmethyl)-amide ¹H NMR (CDCl₃): δ 8.54 (d,J = 4.64 Hz, 1H), 7.65-7.69 (m, 1H), 7.59 (s, 1H), 7.37 (s, 3H),7.16-7.27 (m, 3H), 6.67 (d, J = 8.12 Hz, 1H), 4.55 (d, J = 4.88 Hz, 2H),3.97 (s, 2H), 2.98-3.27 (m, 7H), 2.19-2.46 (m, 6H). Intermediate 1 and2,2- Dimethyl-2,3- dihydro- benzofuran-5- carbaldehyde 33

  1-(2,2-Dimethyl-benzo[1,3]dioxol-5-ylmethyl)- pyrrolidine-3-carboxylicacid (pyridin-2-ylmethyl)-amide ¹H NMR (DMSO-d₆): δ 8.55 (br s, 1H),8.48 (d, J = 6.36 Hz, 1H), 7.72- 7.76 (m, 1H), 7.22-7.26 (m, 2H), 6.79(s, 3H), 4.34 (d, J = 5.88 Hz, 2H), 3.85 (br s, 3H), 3.06 (br s, 4H),2.03 (br s, 2H), 1.62 (s, 6H). Intermediate 1 and 2,2- Dimethyl-benzo[1,3] dioxole-5- carbaldehyde 34

  1-[1-(3-Isobutoxy-benzyl)-pyrrolidin-3- ylmethyl]-1H-imidazole ¹H NMR(DMSO-d₆): δ 8.13 (s, 1H), 7.69 (s, 1H), 7.19 (t, J = 7.44 Hz, 1H),6.78-6.84 (m, 3H), 4.35 (t, J = 6.72 Hz, 2H), 3.71 (d, J = 6.48 Hz, 2H),3.21-3.51 (m, 2H), 2.28-2.66 (m, 3H), 1.41-2.02 (m, 3H), 0.94 (d, J =6.72 Hz, 6H). Intermediate 16 and Intermediate 22 35

2-[1-(3-Isobutoxy-benzyl)-pyrrolidin-3- ylmethoxymethyl]-pyridine ¹H NMR(CDCl3): δ 8.55 (d, J = 4.28 Hz, 1H), 7.68-7.72 (m, 1H), 7.40 (d, J =7.84 Hz, 1H), 7.18-7.27 (m, 2H), 6.82-6.99 (m, 3H), 4.63 (s, 2H), 3.73-3.80 (m, 4H), 3.52-3.54 (m, 2H), 2.54-2.95 (m, 5H), 2.03-2.13 (m, 2H),1.65 (s, 1H), 1.03 (d, J = 6.68 Hz, 6H). Intermediate 20 andIntermediate 22 36

  Pyridine-2-carboxylic acid [1-(3-isopropoxymethyl-benzyl)-pyrrolidin-3-ylmethyl]-amide ¹H NMR (CDCl₃): δ 8.61 (d, J = 4.72Hz, 1H), 8.50 (s, 1H), 8.19 (d, J = 7.80 Hz, 1H), 7.83-7.87 (m, 1H),7.42-7.45 (m, 1H), 6.99-7.24 (m, 3H), 6.81 (d, J = 8.04 Hz, 1H), 3.71-3.72 (m, 4H), 3.47-3.56 (m, 2H), 2.82 (bs, 2H), 2.62 (bs, 3H), 2.03-2.11(m, 2H), 1.67-1.69 (m, IH), 1.01 (d, J = 6.68 Hz, 6H). Intermediate 21and Intermediate 22 37

  (R)-3-methyl-1-(3-phenoxybenzyl)- N-(pyridin-2-ylmethyl)pyrrolidine-3-carboxamide ¹H NMR : 400 MHz, DMSO-d₆: δ 8.41-8.42 (m, 2H), 8.21-8.24(m, 1H), 7.56-7.58 (m, 1H), 7.35-7.39 (m, 2H), 7.27-7.32 (m, 2H), 7.10-7.14 (m, 1H), 7.04 (d, J = 4.80 Hz, 1H), 6.98 (dd, J = 0.96, 1.90 Hz,2H), 6.93-6.94 (m, 1H), 6.85-6.87 (m, 1H), 4.24-4.26 (m, 2H), 3.50-3.58(m, 2H), 2.78 (d, J = 9.20 Hz, 1H), 2.53-2.56 (m, 2H), 2.21-2.32 (m,2H), 1.51-1.56 (m, 1H), 1.21-1.28 (m, 3H). Intermediate 38 and 2-aminomethyl-2- pyridine 38

  (S)-3-methyl-1-(3-phenoxybenzyl)-N- (pyridin-2-ylmethyl)pyrrolidine-3-carboxamide ¹H NMR: 400 MHz, DMSO-d₆: δ 8.41-8.42 (m, 2H), 8.21-8.24(m, 1H), 7.56-7.58 (m, 1H), 7.35-7.39 (m, 2H), 7.27-7.32 (m, 2H), 7.10-7.14 (m, 1H), 7.04 (d, J = 4.80 Hz, 1H), 6.98 (dd, J = 0.96, 1.90 Hz,2H), 6.93-6.94 (m, 1H), 6.85-6.87 (m, 1H), 4.24-4.26 (m, 2H), 3.50-3.58(m, 2H), 2.78 (d, J = 9.20 Hz, 1H), 2.53-2.56 (m, 2H), 2.21-2.32 (m,2H), 1.51-1.56 (m, 1H), 1.21-1.28 (m, 3H). Intermediate 38 and 2-aminomethyl-2- pyridine 39

  [3-Methyl-1-(3-phenoxy-benzyl)-pyrrolidin-3-yl]-piperazin-1-yl-methanone ¹H NMR: 400 MHz, DMSO-d₆: δ 7.36-7.40 (m, 2H),7.29-7.33 (m, 1H), 7.11-7.15 (m, 1H), 7.04-7.05 (m, 1H), 6.98-7.01 (m,2H), 6.92- 0.00 (m, 1H), 6.86-6.88 (m, 1H), 3.50 (s, 2H), 3.32-3.40 (m,4H), 3.01-3.12 (m, 1H), 2.85 (d, J = 9.32 Hz, 1H), 2.85-2.63 (m, 4H),2.30- 2.38 (m, 2H), 2.15-2.21 (m, 1H), 1.64-1.70 (m, 1H), 1.22 (s, 4H).LCMS: 380.2 (M + H), Rt. 2.9 min, 96.2% (max), 95.9% (220 nm).Intermediate 38 and piperizine 40

3-Methyl-1-(3-phenoxy-benzoyl)-pyrrolidine- 3-carboxylic acid ethylamide¹H NMR: 400 MHz, DMSO-d₆: δ 7.72-7.73 (m, 1H), 7.39-7.47 (m, 3H),7.15-7.25 (m, 2H), 7.02-7.10 (m, 4H), 3.72-3.79 (m, 1H), 3.40- 3.46 (m,2H), 3.14-3.27 (m, 1H), 3.02-3.09 (m, 2H), 1.98-2.00 (m, 1H), 1.73-1.78(m, 1H), 1.23-1.25 (m, 3H), 0.94-1.01 (m, 3H). Intermediate 40 andethylamine 41

  3-Methyl-1-(3-trifluoromethoxy- benzyl)-pyrrolidine-3-carboxylic acidethylamide ¹H NMR: 400 MHz, DMSO-d₆: δ 7.55-7.58 (m, 1H), 7.43-7.47 (m,1H), 7.31-7.36 (m, 1H), 7.28-0.00 (m, 1H), 7.21-7.24 (m, 1H), 3.60- 0.00(m, 2H), 3.02-3.08 (m, 2H), 2.75 (d, J = 9.16 Hz, 1H), 2.53-2.57 (m,2H), 2.19-2.25 (m, 2H), 1.48- 1.54 (m, 1H), 1.19-1.54 (m, 3H), 0.96-0.99(m, 3H). Intermediate 42 and ethylamine 42

  1-[3-(2-Methyl-propane-1-sulfinyl)-benzyl]- pyrrolidine-3-carboxylicacid (pyridin-2-ylmethyl)-amide ¹H NMR: 400 MHz, DMSO-d₆: δ 8.47-8.48(m, 1H), 8.41 (t, J = 5.84 Hz, 1H), 7.73 (s, 1H), 7.61-0.00 (m, 1H),7.45-7.53 (m, 3H), 7.19-7.25 (m, 2H), 4.33 (d, J = 5.92 Hz, 2H), 3.65(s, 2H), 2.60-3.16 (m, 5H), 2.42- 2.45 (m, 2H), 1.91-2.07 (m, 3H), 1.07(d, J = 6.64 Hz, 3H), 0.96-0.97 (m, 3H). LCMS: 400.2 (M + 1), Rt. 2.01min, 96.8% (max), 97.7% (254 nm). Intermediate 2 and Intermediate 60 43

  1-(3-m-Tolyloxy-benzyl)-pyrrolidine-3- carboxylic acid(pyridin-2-ylmethyl)-amide 400 MHz, DMSO-d₆: 8.47 (d, J = 4.76 Hz, 1H),8.40 (t, J = 6.08 Hz, 1H), 7.75-7.70 (m, 1H), 7.32-7.19 (m, 4H), 7.06(d, J = 7.56 Hz, 1H), 6.95-6.93 (m, 2H), 6.86-6.76 (m, 3H), 4.32 (d, J =5.84 Hz, 2H), 3.55 (s, 2H), 2.94-2.90 (m, 1H), 2.78 (t, J = 8.24 Hz,1H), 2.65-2.55 (m, 2H), 2.48-2.30 (m, 1H), 2.27 (s, 3H), 1.95- 1.91 (m,2H). Intermediate 2 and 3-m- tolyloxy benzaldehyde 44

  1-[3-(Pyrimidin-2-yloxy)-benzyl]-pyrrolidine- 3-carboxylic acid(pyridin-2-ylmethyl)-amide 400 MHz, MeOD: 8.60 (d, J = 4.80 Hz, 2H),8.49 (d, J = 4.24 Hz, 1H), 7.83-7.79 (m, 1H), 7.52 (t, J = 7.84 Hz, 1H),7.40-7.30 (m, 4H), 7.27- 7.22 (m, 2H), 4.54-4.46 (m, 2H), 4.27-4.19 (m,2H), 3.32-3.24 (m, 5H), 2.39-2.33 (m, 1H), 2.24-2.19 (m, 1H).Intermediate 2 and 3- pyrimidin- 2yloxy- benzaldehyde 45

  3-Methyl-1-(3-m-tolyloxy-benzyl)- pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide 400 MHz, MeOD: 8.48-8.47 (m, 1H), 7.81-7.76(m, 1H), 7.39-7.28 (m, 3H), 7.23 (t, J = 7.84 Hz, 1H), 7.16 (d, J = 7.56Hz, 1H), 7.10 (s, 1H), 6.99-6.95 (m, 2H), 6.82 (s, 1H), 6.78-6.76 (m,1H), 4.48 (s, 2H), 4.10- 3.90 (m, 2H), 3.60-3.50 (m, 1H), 3.05-2.43 (m,4H), 2.31 (s, 3H), 2.00- 1.90 (m, 1H), 1.42 (s, 3H). Intermediate 6 and3-m- tolyloxy- benzaldehyde

Example 2 1-(3-Isobutylsulfanyl-benzyl)-pyrrolidine-3-carboxylic acidpyridin-2-ylmethyl ester (46)

1-Chloromethyl-3-isobutylsulfanyl-benzene (Intermediate 12, 0.23 g, 1.09mmol) was taken in dry DMF (10 mL) and potassium carbonate (0.45 g, 3017mmol), and Pyrrolidine-3-carboxylic acid (pyridin-2-ylmethyl)-amidehydrochloride (Intermediate 1, 0.31 g, 1.31 mmol) were added, and thereaction mixture was stirred at room temperature for 12 h. The reactionmixture was filtered through celite and concentrated under reducedpressure to provide the crude product which was purified by columnchromatography (pet ether/ethyl acetate 20%). Yield: 15% (65 mg,colorless liquid); ¹H NMR: 400 MHz, (DMSO-d₆): δ 8.40-8.48 (m, 2H),7.71-7.75 (m, 1H), 7.08-7.25 (m, 6H), 4.33 (d, J=5.88 Hz, 2H), 3.53 (s,2H), 2.39-2.95 (m, 7H), 1.73-1.96 (m, 3H), 0.96 (d, J=6.64 Hz, 6H).

The following compounds were synthesized according to the procedure inExample 2 from the starting materials indicated in the table.

Starting Cmpd Structure Data Materials 47

¹H NMR (DMSO-d₆): δ 8.47 (d, J = 4.80 Hz, 1H), 8.40-8.41 (m, 1H), 7.83(s, 1H), 7.57-7.78 (m, 4H), 7.19-7.25 (m, 2H), 4.33 (d, J = 5.88 Hz,2H), 3.68 (s, 2H), 3.19 (d, J = 6.64 Hz, 2H), 2.49-2.97 (m, 5H), 0.94(d, J = 6.72 Hz, 6H). Intermediate 1 and Intermediate 151-[3-(2-Methyl-propane-1-sulfonyl)-benzyl]-pyrrolidine- 3-carboxylicacid pyridin-2-ylmethyl ester

Example 32-{3-[1-(3-Isobutoxy-benzyl)-pyrrolidin-3-yl]-[1,2,4]oxadiazol-5-yl}-pyridine(48)

N-Hydroxy-1-(3-isobutoxy-benzyl)-pyrrolidine-3-carboxamidine(Intermediate 26, 0.2 g, 0.69 mmol) was taken in dry THF (3 mL) and tothis was added picolinic acid (0.1 g, 0.83 mmol), triethyl amine (0.29mL, 2.07 mmol) and 50% solution of T3P in ethyl acetate (0.64 mL, 1.03mmol). The reaction mixture was heated to reflux at 10 h. The reactionmixture was cooled to room temperature and treated with 10% aqueoussolution of sodium bicarbonate, and extracted with ethyl acetate. Theorganic layer was washed with brine and dried over anhydrous sodiumsulphate to get the crude material, which was purified by columnchromatography (pet ether/ethyl acetate 20%) to provide the titledcompound as a colorless gummy solid (12%, 33 mg). ¹H NMR: (DMSO-d₆): δ8.80 (s, 1H), 8.22 (d, J=7.88 Hz, 1H), 8.07-8.09 (m, 1H), 7.68-7.71 (m,1H), 7.20 (t, J=8.00 Hz, 1H), 6.87 (t, J=7.16 Hz, 2H), 6.68-6.78 (m,1H), 3.55-3.70 (m, 5H), 1.95-2.94 (m, 7H), 0.94 (d, J=6.72 Hz, 6H).LCMS: 379.2 (M+1), Rt. 3.82 min, 91.7% (max), 99.1% (254 nm).

The following Examples were synthesized according to the proceduredescribed for Example 3 from the starting materials listed in the table.

Starting Cmpd Structure Data Materials 49

¹H NMR: (DMSO-d₆): δ 8.34-8.35 (m, 1H), 7.61-7.81 (m, 2H), 7.17- 7.21(m, 1H), 6.77-6.87 (m, 3H), 3.93 (s, 3H), 3.54-3.70 (m, 5H), 2.62-2.96(m, 3H), 1.95-2.31 (m, 3H), 0.94 (d, J = 6.68 Hz, 6H). LCMS: 409.2 (M +1), Rt. 3.82 min, 98.4% (max), 98.4% (220 nm). Intermediate 26 and2-hydroxy- picolinc acid 2-{3-[1-(3-Isobutoxy-benzyl)-pyrrolidin-3-yl]-[1,2,4]oxadiazol- 5-yl}-3-methoxy-pyridine 50

¹H NMR: (DMSO-d₆): δ 8.67-8.68 (m, 1H), 8.04-8.09 (m, 1H), 7.81- 7.85(m, 1H), 7.20 (t, J = 7.96 Hz, 1H), 6.86-6.88 (m, 2H), 6.77-6.79 (m,1H), 3.55-3.70 (m, 5H), 2.92- 2.97 (m, 1H), 2.64-2.75 (m, 3H), 2.25-2.29(m, 1H), 1.93-2.15 (m, 2H), 0.94 (d, J = 6.68 Hz, 6H). LCMS: 397.2 (M +1), Rt. 3.84 min, 92.8% (max). Intermediate 26 and 2-fluoro- picolinicacid 3-Fluoro-2-{3-[1-(3-isobutoxy-benzyl)-pyrrolidin-3-yl]-[1,2,4]oxadiazol- 5-yl}-pyridine 51

¹H NMR: (DMSO-d₆): δ 8.62-8.63 (m, 1H), 7.91-7.93 (m, 1H), 7.57- 7.60(m, 1H), 7.17-7.21 (m, 1H), 6.86-6.88 (m, 3H), 3.54-3.70 (m, 5H),1.94-2.94 (m, 9H), 0.94 (d, J = 6.68 Hz, 6H). LCMS: 393.0 (M + 1), Rt.4.01 min, 96.2% (max), 95.6% (220 nm). Intermediate 26 and 2-methyl-picolinic acid 2-{3-[1-(3-Isobutoxy-benzyl)-pyrrolidin-3-yl]-[1,2,4]oxadiazol- 5-yl}-3-methyl-pyridine 52

¹H NMR: (DMSO-d₆): δ 8.59 (s, 1H), 7.69-7.70 (m, 1H), 7.18-7.28 (m, 2H),6.77-6.88 (m, 3H), 3.94 (s, 3H), 3.55-3.70 (m, 5H), 2.92-2.96 (m, 1H),2.59-2.74 (m, 3H), 1.95-2.48 (m, 3H), 0.94 (d, J = 6.68 Hz, 6H).Intermediate 26 and 4-methoxy- picolinic acid2-{3-[1-(3-Isobutoxy-benzyl)- pyrrolidin-3-yl]-[1,2,4]oxadiazol-5-yl}-4-methoxy-pyridine 53

¹H NMR: (DMSO-d₆): δ 8.78 (d, J = 5.28 Hz, 1H), 8.27 (d, J = 2.00 Hz,1H), 7.87-7.88 (m, 1H), 7.18-7.21 (m, 1H), 6.86-6.87 (m, 2H), 6.77- 6.80(m, 1H), 3.55-3.70 (m, 5H), 2.92-2.96 (m, 1H), 2.62-2.74 (m, 3H),2.10-2.31 (m, 2H), 1.95-1.98 (m, 1H), 0.94 (d, J = 6.68 Hz, 6H).Intermediate 26 and 4-chloro- picolinic acid4-Chloro-2-{3-[1-(3-isobutoxy- benzyl)-pyrrolidin-3-yl]-[1,2,4]oxadiazol-5-yl}-pyridine 54

¹H NMR: (DMSO-d₆): δ 8.18-8.48 (m, 2H), 7.59-7.62 (m, 1H), 7.17- 7.21(m, 1H), 6.77-6.87 (m, 3H), 3.93 (s, 3H), 3.62-3.86 (m, 5H), 1.95-2.96(m, 5H), 0.94 (d, J = 6.68 Hz, 6H). Intermediate 26 and 5-methoxy-picolinic acid 2-{3-[1-(3-Isobutoxy-benzyl)-pyrrolidin-3-yl]-[1,2,4]oxadiazol- 5-yl}-5-methoxy-pyridine 55

¹H NMR: (DMSO-d₆): δ 8.65 (s, 1H), 8.12 (d, J = 7.96 Hz, 1H), 7.88 (d, J= 8.36 Hz, 1H), 7.20 (t, J = 7.16 Hz, 1H), 6.77-6.87 (m, 3H), 3.58-3.70(m, 5H), 2.71-2.96 (m, 1H), 1.93- 2.66 (m, 7H), 0.94 (d, J = 6.68 Hz,6H). Intermediate 26 and 5-methyl- picolinic acid2-{3-[1-(3-Isobutoxy-benzyl)- pyrrolidin-3-yl]-[1,2,4]oxadiazol-5-yl}-5-methyl-pyridine 56

¹H NMR: (DMSO-d₆): δ 7.93-7.97 (m, 1H), 7.84 (d, J = 6.76 Hz, 1H),7.13-7.22 (m, 2H), 6.86-6.87 (m, 2H), 6.77-6.79 (m, 1H), 3.95 (s, 3H),3.54-3.70 (m, 5H), 2.91-2.95 (m, 1H), 2.62-2.75 (m, 3H), 2.24-2.28 (m,1H), 1.93-2.12 (m, 2H), 0.94 (d, J = 6.68 Hz, 6H). Intermediate 26 and6-methoxy- picolinic acid 2-{3-[1-(3-Isobutoxy-benzyl)-pyrrolidin-3-yl]-[1,2,4]oxadiazol- 5-yl}-6-methoxy-pyridine 57

¹H NMR: (DMSO-d₆): δ 8.48-8.49 (m, 1H), 7.78-7.82 (m, 1H), 7.16- 7.45(m, 3H), 6.77-6.85 (m, 3H), 4.47 (s, 2H), 3.33-3.71 (m, 5H), 2.88 (t, J= 8.84 Hz, 1H), 2.54-2.66 (m, 3H), 2.15-2.21 (m, 1H), 1.93-2.01 (m, 2H),0.95-0.97 (m, 6H). LCMS: 393.2 (M + 1), Rt. 3.29 min, 93.1% (max), 93.3%(220 nm). Intermediate 26 and 3-pyridyl- benzoic acid2-{3-[1-(3-Isobutoxy-benzyl)- pyrrolidin-3-yl]-[1,2,4]oxadiazol-5-ylmethyl}-pyridine 58

¹H NMR: 400 MHz, DMSO-d₆: δ 8.69 (d, J = 5.04 Hz, 1H), 8.38 (d, J = 1.68Hz, 1H), 8.00-8.02 (m, 1H), 7.18-7.22 (m, 1H), 6.86-6.87 (m, 2H),6.77-6.80 (m, 1H), 3.55-3.70 (m, 5H), 2.92-2.96 (m, 1H), 2.66- 2.74 (m,3H), 2.24-2.28 (m, 1H), 1.93-2.13 (m, 2H), 0.94 (d, J = 6.68 Hz, 6H).LCMS: 457.0 (M + 1), Rt. 4.23 min, 90.8% (max), 94.2% (254 nm).Intermediate 26 and 4-bromo- picolinic acid4-Bromo-2-{3-[1-(3-isobutoxy-benzyl)- pyrrolidin-3-yl]-[1,2,4]oxadiazol-5-yl}-pyridine 59

¹H NMR: 400 MHz, DMSO-d₆: δ 8.83 (s, 1H), 8.30-8.33 (m, 1H), 7.99- 8.03(m, 1H), 7.18-7.22 (m, 1H), 6.77-6.87 (m, 3H), 3.55-3.70 (m, 5H), 2.94(s, 1H), 2.61-2.74 (m, 3H), 1.95-2.31 (m, 3H), 0.94 (d, J = 6.68 Hz,6H). Intermediate 26 and 5-fluoro- picolinic acid5-Fluoro-2-{3-[1-(3-isobutoxy-benzyl)-pyrrolidin-3-yl]-[1,2,4]oxadiazol- 5-yl}-pyridine

Example 42-{1-[1-(3-Isobutoxy-benzyl)-pyrrolidin-3-yl]-1H-[1,2,3]triazol-4-yl}-pyridine(60)

3-Azido-1-(3-isobutoxy-benzyl)-pyrrolidine (Intermediate 27, 0.4 g, 1.46mmol) was taken in a mixture of solvents: t-butanol (4 mL) and water (1mL). To this was added copper sulphate pentahydrate (0.01 g, 0.07 mmol),sodium ascorbate (0.03 g, 0.17 mmol), and 2-Ethynyl-pyridine (0.15 g,1.46 mmol) and stirred at room temperature for 15 h. The reactionmixture was concentrated under reduced pressure and the titled compoundwas obtained by purification by column chromatography (pet ether/ethylacetate 20%) to give the desired product (4%, 20 mg, colorless liquid).¹H NMR: (DMSO-d₆): δ 8.62 (s, 1H), 8.58-8.59 (m, 1H), 8.02 (d, J=7.92Hz, 1H), 7.86-7.91 (m, 1H), 7.32-7.35 (m, 1H), 7.18-7.22 (m, 1H),6.77-6.88 (m, 3H), 5.28 (s, 1H), 3.59-3.70 (m, 4H), 2.81-3.00 (m, 3H),2.17-2.50 (m, 3H), 1.90-1.97 (m, 1H), 0.91 (d, J=6.72 Hz, 6H). LCMS:(Method B) 378.3 (M+1), Rt. 6.54 min, 90.3% (max), 85.0% (220 nm).

The following Examples were synthesized according to the proceduredescribed for Example 4 from the starting materials listed in the table.

Starting Cmpd Structure Data Materials 61

¹H NMR: (DMSO-d₆): δ 8.56 (s, 1H), 7.74-7.83 (m, 2H), 7.18-7.22 (m, 2H),6.77-6.88 (m, 3H), 5.28 (d, J = 6.28 Hz, 2H), 3.63-3.70 (m, 4H),2.84-2.98 (m, 3H), 1.91-2.17 (m, 2H), 0.91 (d, J = 6.68 Hz, 6H). LCMS:392.2 (M + 1), Rt. 3.11 min, 95.3% (max), 94.2% (220 nm). Intermediate27 and 6-methyl-2- ethynyl-pyridine2-{1-[1-(3-Isobutoxy-benzyl)-pyrrolidin-3-yl]-1H-[1,2,3]triazol-4-yl}-6-methyl-pyridine 62

¹H NMR: (DMSO-d₆): δ 8.57 (s, 1H), 7.76-7.80 (m, 1H), 7.60 (d, J = 7.36Hz, 1H), 7.19 (t, J = 8.04 Hz, 1H), 6.88-6.90 (m, 2H), 6.75-6.80 (m,2H), 5.28 (d, J = 2.52 Hz, 1H), 3.93 (s, 3H), 3.58-3.71 (m, 4H),2.81-2.99 (m, 3H), 2.14-2.18 (m, 1H), 1.90- 1.95 (m, 1H), 0.91 (d, J =6.68 Hz, 6H). Intermediate 27 and 6-methoxy- 2-ethynyl- pyridine2-{1-[1-(3-Isobutoxy-benzyl)-pyrrolidin-3-yl]-1H-[1,2,3]triazol-4-yl}-6-methoxy-pyridine 63

¹H NMR: (DMSO-d₆): δ 8.66 (s, 1H), 8.04 (d, J = 7.56 Hz, 1H), 7.84 (t, J= 7.80 Hz, 1H), 7.59 (d, J = 7.80 Hz, 1H), 7.20 (t, J = 8.00 Hz, 1H),6.86- 6.87 (m, 2H), 6.76-6.79 (m, 1H), 5.28 (d, J = 6.32 Hz, 1H),3.59-3.70 (m, 4H), 2.84-2.99 (m, 3H), 1.92-2.21 (m, 2H), 0.90 (d, J =6.68 Hz, 6H). Intermediate 27 and 6-bromo-2- ethynyl-pyridine2-Bromo-6-{1-[1-(3-isobutoxy-benzyl)-pyrrolidin-3-yl]-1H-[1,2,3]triazol-4-yl}-pyridine

Example 5{5-[1-(3-Isobutoxy-benzyl)-pyrrolidin-3-yl]-[1,3,4]oxadiazol-2-yl}-methanol(64)

Acetic acid5-[1-(3-isobutoxy-benzyl)-pyrrolidin-3-yl]-[1,3,4]oxadiazol-2-ylmethylester (Intermediate 31, 0.1 g, 0.27 mmol) was taken in methanol (3 mL)and water (1 mL) and to this was added potassium carbonate (0.05 g, 0.40mmol) and stirred for 2 h at room temperature. The reaction mixture wasconcentrated under reduced pressure and the resulting crude mass wasdiluted with ethyl acetate, washed with water, brine, dried over sodiumsulfate, and concentrated under reduced pressure to provide the crudeproduct. Purification by column chromatography (pet ether/ethyl acetate35%) provided the titled compound as a colorless oil (45%, 40 mg). ¹HNMR: (DMSO-d₆): δ 7.17-7.21 (m, 1H), 6.84-6.86 (m, 2H), 6.77-6.80 (m,1H), 5.83 (t, J=6.20 Hz, 1H), 4.58 (d, J=6.20 Hz, 2H), 3.53-3.70 (m,5H), 2.86-2.90 (m, 1H), 2.69-2.73 (m, 1H), 2.58-2.62 (m, 2H), 2.21-2.25(m, 1H), 1.95-2.08 (m, 2H), 0.96 (d, J=6.72 Hz, 6H). LCMS: 332.3 (M+1),Rt. 3.04 min, 93.9% (max), 93.9% (220 nm).

Example 6

The following compounds were synthesized according to one of the generalprocedure below from the starting materials listed in the table below.

To a 10 ml microwave vial with stir bar was added amine (0.270 g, 1.5equiv) and DABAL-Me3 (0.540 mg, 1.2 equiv). Reagents were suspended inTHF (4 ml) and run in microwave reactor at 130° C. for 20 min. Thereaction mixture was cooled to room temperature and to it was added theappropriate Intermediate (0.500 g. 1 equiv). The reaction mixture wasirradiated in microwave reactor at 130° C. for 20 min. After allowing tocool down to room temperature the reaction mixture was quenched by theaddition of 2M HCl. The reaction mixture was extracted with ethylacetate. The combined organic layer was washed with water (20 ml) andbrine solution then dried over anhydrous sodium sulfate and evaporatedunder reduced pressure. The crude residue was purified by columnchromatography using petroleum ether-ethyl acetate as eluents to get thepure amide.

A solution of amine (1 equiv) in 10 mL of dichloromethane was mixed withIntermediate 34 or 35 (1.2 equiv) and Et₃N (3 equiv). T3P (3 equiv) wasadded to the reaction mixture at 0 OC. The reaction mixture was stirredat room temperature for 12 h. The reaction mixture was diluted withdichloromethane (20 mL) and washed with 10% NaHCO3 solution (1×20 mL),water (1×20 mL), followed by brine solution (lx 20 mL), then dried overanhydrous sodium sulphate, filtered and evaporated. The residue waspurified by column chromatography on silica gel to get the amideproduct.

Starting Cmpd Structure Data Materials 65

¹H NMR (400 MHz, DMSO-d₆): δ 7.37-7.26 (m, 5H), 7.24-7.22 (m, 1H),7.15-7.12 (m, 1H), 7.07 (br s, 1H), 7.02-7.00 (m, 2H), 6.97-6.88 (m,3H), 6.75 (br s, 1H), 4.40 (d, J = 5.76 Hz, 2H), 3.97 (br s, 2H), 3.82(br s, 3H), 3.09-2.96 (m, 5H), 2.37 (br s, 1H), 2.11 (br s, 1H). LCMS:417.3 (m + 1), RT(4.12) min, 95.30% (Max), 95.28% (220 nm). Intermediate32 and 2- methoxybenzyl amine 1-(3-Phenoxy-benzyl)-pyrrolidine-3-carboxylic acid 2-methoxy-benzylamide 66

¹H NMR (400 MHz, DMSO-d₆): δ 8.22 (br s, 1H), 7.40-7.35 (m, 2H), 7.31(t, J = 7.84 Hz, 1H), 7.14-7.11 (m, 3H), 7.07-7.05 (m, 1H), 7.00-6.98(m, 2H), 6.94 (br s, 1H), 6.87-6.83 (m, 3H), 4.16 (d, J = 5.84 Hz, 2H),3.71 (s, 3H), 3.54 (brs, 2H), 2.87-2.76 (m, 2H), 2.67-2.60 (m, 1H), 2.39(br s, 2H), 1.91-1.87 (m, 2H). Intermediate 32 and 4- methoxybenzylamine 1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid4-methoxy-benzylamide 67

¹H NMR (400 MHz, DMSO-d₆): δ 10.75-10.30 (m, 1H), 8.77 (s, 1H),7.45-7.30 (m, 8H), 7.16 (t, J = 7.40 Hz, 1H), 7.05-7.03 (m, 3H),4.38-4.29 (m, 3H), 3.60- 3.49 (m, 1H), 3.18 (br s, 2H), 2.46-2.38 (m,3H), 2.17 (br s, 1H), 2.11-1.89 (m, 1H). Intermediate 32 and 4-trifuoromethoxy benzylamine 1-(3-Phenoxy-benzyl)-pyrrolidine-3-carboxylic acid 4-trifluoromethoxy-benzylamide 68

¹H NMR (400 MHz, DMSO-d₆): δ 10.92 (brs, 1H), 8.71 (brs, 1H), 7.47-7.36(m, 5H), 7.26-7.24 (m, 3H), 7.17-7.13 (m, 1H), 7.03- 7.02 (m, 3H),4.64-4.24 (m, 3H), 3.61-3.49 (m, 2H), 3.14-2.98 (m, 2H), 2.29-1.92 (m,4H). LCMS: 421.0 (m + 1), RT(4.47) min, 98.13% (Max), 98.22%(220 nm).Intermediate 32 and 4- chlorobenzyl- amine1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid 4-chloro-benzylamide69

¹H NMR (400 MHz, CD₃OD): δ 7.45-7.36 (m, 3H), 7.33-7.25 (m, 3H),7.22-7.20 (m, 2H), 7.18- 7.14 (m, 2H), 7.05-7.00 (m, 3H), 4.36 (s, 2H),4.23-4.14 (m, 2H), 3.35-3.31 (m, 2H), 3.23-3.20 (m, 3H), 2.37-2.31 (m,1H), 2.19- 2.13 (m, 1H). Intermediate 32 and 3- chlorobenzyl- amine1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid 3-chloro-benzylamide70

¹H NMR (400 MHz, CD₃OD): δ 7.58-7.52 (m, 4H), 7.39-7.34 (m, 3H),7.16-7.11 (m, 2H), 7.07 (br s, 1H), 7.01-6.96 (m, 3H), 4.47- 4.40 (m,2H), 3.94-3.91 (m, 2H), 3.14-3.12 (m, 2H), 2.99-2.79 (m, 3H), 2.22-2.20(m, 1H), 2.12- 2.08 (m, 1H). Intermediate 32 and 3- trifluoromethylbenzylamine 1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid3-trifluoromethyl-benzylamide 71

¹H NMR (400 MHz, CD₃OD): δ 7.62 (d, J = 8.12 Hz, 2H), 7.44 (d, J = 8.08Hz, 2H), 7.37-7.29 (m, 3H), 7.13-7.09 (m, 2H), 7.02- 6.96 (m, 3H),6.92-6.89 (m, 1H), 4.43 (s, 2H), 3.72-3.63 (m, 2H), 3.02-2.92 (m, 2H),2.81-2.76 (m, 1H), 2.69-2.59 (m, 2H), 2.13- 2.09 (m, 2H). Intermediate32 and 4- trifluoromethyl benzylamine1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid4-trifluoromethyl-benzylamide 72

¹H NMR (400 MHz, CD₃OD): δ 7.71 (d, J = 7.80 Hz, 1H), 7.61 (t, J = 7.40Hz, 1H), 7.52 (d, J = 7.76 Hz, 1H), 7.48-7.36 (m, 4H), 7.23 (d, J = 7.64Hz, 1H), 7.18-7.13 (m, 2H), 7.06-7.01 (m, 3H), 4.62- 4.54 (m, 2H),4.27-4.18 (m, 2H), 3.38-3.36 (m, 2H), 3.31-3.24 (m, 3H), 2.42-2.32 (m,1H), 2.23- 2.14 (m, 1H). LCMS: 455.3 (m + 1), RT(4.45) min, 96.28%(Max), 96.25%(220 nm). Intermediate 32 and 2- trifluoromethylbenzylanine 1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid2-trifluoromethyl-benzylamide 73

¹H NMR (400 MHz, CD₃OD): δ 7.71 (d, J = 7.80 Hz, 1H), 7.61 (t, J = 7.40Hz, 1H), 7.52 (d, J = 7.76 Hz, 1H), 7.48-7.36 (m, 4H), 7.23 (d, J = 7.64Hz, 1H), 7.18-7.13 (m, 2H), 7.06-7.01 (m, 3H), 4.62- 4.54 (m, 2H),4.27-4.18 (m, 2H), 3.38-3.36 (m, 2H), 3.31-3.24 (m, 3H), 2.42-2.32 (m,1H), 2.23- 2.14 (m, 1H). Intermediate 32 and 2- fluorobenzyl- amine1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid 2-fluoro-benzylamide74

¹H NMR (400 MHz, CD₃OD): δ 7.38-7.30 (m, 4H), 7.15-7.13 (m, 2H),7.11-7.06 (m, 2H), 7.02- 6.97 (m, 5H), 4.36 (s, 2H), 3.92- 3.83 (m, 2H),3.12-3.07 (m, 2H), 2.99-2.93 (m, 2H), 2.92-2.84 (m, 1H), 2.23-2.18 (m,1H), 2.12- 2.11 (m, 1H). Intermediate 32 and 3- fluorobenzyl- amine1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid 3-fluoro-benzylamide75

¹H NMR (400 MHz, CD₃OD): δ 7.36-7.25 (m, 5H), 7.13-6.96 (m, 7H),6.91-6.88 (m, 1H), 4.91 (s, 2H), 3.67-3.59 (m, 2H), 2.99- 2.95 (m, 1H),2.93-2.87 (m, 1H), 2.78-2.72 (m, 1H), 2.62-2.54 (m, 2H), 2.11-2.09 (m,2H). LCMS: 405.3 (m + 1), RT(4.18) min, 99.46% (Max), 99.46%(220 nm).Intermediate 32 and 4- fluorobenzyl- amine1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid 4-fluoro-benzylamide76

¹H NMR (400 MHz, CD₃OD): δ 7.37-7.29 (m, 3H), 7.13-7.09 (m, 2H),7.01-6.96 (m, 3H), 6.91- 6.80 (m, 4H), 4.35 (s, 2H), 3.69- 3.60 (m, 2H),3.02-2.90 (m, 2H), 2.79-2.73 (m, 1H), 2.64-2.55 (m, 2H), 2.13-2.02 (m,2H). Intermediate 32 and 3,5- difluorobenzl- amine1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid3,5-difluoro-benzylamide 77

¹H NMR (400 MHz, DMSO-d₆): δ 8.18 (t, J = 5.00 Hz, 1H), 7.41- 7.35 (m,3H), 7.33-7.28 (m, 1H), 7.14-7.11 (m, 1H), 7.10-7.04 (m, 3H), 7.00-6.98(m, 2H), 6.93 (s, 1H), 6.87-6.85 (m, 1H), 4.28 (d, J = 5.24 Hz, 2H),3.54 (s, 2H), 2.82-2.76 (m, 2H), 2.61-2.60 (m, 1H), 2.37-2.32 (m, 2H),1.87- 1.84 (m, 2H). Intermediate 32 and 2,5- difuorobenzyl- amine1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid2,5-difluoro-benzylamide 78

¹H NMR (400 MHz, CD₃OD): δ 7.42-7.33 (m, 4H), 7.20-7.10 (m, 3H),7.03-7.00 (m, 3H), 6.98- 6.90 (m, 2H), 4.42-4.34 (m, 2H), 4.17-4.03 (m,2H), 3.24-3.07 (m, 5H), 2.32-2.23 (m, 1H), 2.15- 2.07 (m, 1H). LCMS:423.0 (m + 1), RT(4.15) min, 98.85% (Max), 98.70%(220 nm). Intermediate32 and 2,4- difluorobenzyl- amine 1-(3-Phenoxy-benzyl)-pyrrolidine-3-carboxylic acid 2,4-difluoro-benzylamide 79

¹H NMR (400 MHz, CD₃OD): δ 7.43-7.32 (m, 4H), 7.20-7.11 (m, 3H),7.03-6.96 (m, 5H), 4.51- 4.43 (m, 2H), 4.15-4.07 (m, 2H), 3.25-3.12 (m,5H), 2.28-2.23 (m, 1H), 2.13-2.06 (m, 1H). Intermediate 32 and 2,6-difluorobenzyl- amine 1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylicacid 2,6-difluoro-benzylamide 80

¹H NMR (400 MHz, CD₃OD): δ 7.36-7.29 (m, 3H), 7.23-7.04 (m, 5H),7.00-6.96 (m, 3H), 6.91- 6.88 (m, 1H), 4.31 (s, 2H), 3.68- 3.60 (m, 2H),3.31-2.88 (m, 2H), 2.78-2.73 (m, 1H), 2.63-2.55 (m, 2H), 2.12-1.99 (m,2H). Intermediate 32 and 3,4- difluorobenzyl- amine1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid3,4-difluoro-benzylamide 81

¹H NMR (400 MHz, CD₃OD): δ 7.36-7.28 (m, 5H), 7.19-7.17 (m, 2H),7.12-7.07 (m, 2H), 6.99- 6.96 (m, 3H), 6.90-6.88 (m, 1H), 4.30 (s, 2H),3.67-3.58 (m, 2H), 2.98-2.87 (m, 2H), 2.75-2.71 (m, 1H), 2.63-2.54 (m,2H), 2.08- 2.02 (m, 2H), 1.30 (s, 9H). Intermediate 32 and 4-tert-butylbenzyl- amine 1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid4-tert-butyl-benzylamide 82

¹H NMR (400 MHz, DMSO-d₆): δ 8.26 (t, J = 5.04 Hz, 1H), 7.40- 7.36 (m,2H), 7.33-7.29 (m, 1H), 7.19-7.11 (m, 2H), 7.07-6.98 (m, 6H), 6.94 (s,1H), 6.88-6.86 (m, 1H), 4.19 (d, J = 5.88 Hz, 2H), 3.55 (s, 2H),2.89-2.85 (m, 1H), 2.80-2.76 (m, 1H), 2.66-2.56 (m, 1H), 2.47-2.32 (m,2H), 2.26 (s, 3H), 1.92-1.89 (m, 2H). Intermediate 34 and 3-methylbenzyl- amine 1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid3-methyl-benzylamide 83

¹H NMR (400 MHz, CD₃OD): δ 7.36-7.28 (m, 3H), 7.13-7.07 (m, 6H),6.99-6.97 (m, 3H), 6.91- 6.89 (m, 1H), 4.29 (s, 2H), 3.68- 3.59 (m, 2H),2.98-2.87 (m, 2H), 2.78-2.72 (m, 1H), 2.63-2.54 (m, 2H), 2.31 (s, 3H),2.10-2.02 (m, 2H). LCMS: 401.3(m + 1), RT(4.25) min, 94.65% (Max),94.48%(220 nm). Intermediate 34 and 4- methylbenzyl- amine1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid 4-methyl-benzylamide84

¹H NMR (400 MHz, CD₃OD): δ 7.36-7.29 (m, 3H), 7.17-7.08 (m, 3H),7.01-6.85 (m, 6H), 4.32 (s, 2H), 3.75-3.67 (m, 2H), 3.06- 2.95 (m, 2H),2.84-2.79 (m, 1H), 2.74-2.63 (m, 2H), 2.26 (s, 3H), 2.16-2.14 (m, 2H).Intermediate 32 and 5-fluoro-2- methylbenzyl- amine1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid5-fluoro-2-methyl-benzylamide 85

¹H NMR (400 MHz, CD₃OD): δ 7.90-7.88 (m, 2H), 7.69 (s, 1H), 7.43-7.39(m, 2H), 7.35-7.28 (m, 4H), 7.11-7.08 (m, 2H), 7.02 (s, 1H), 6.98-6.96(m, 2H), 6.90- 6.88 (m, 1H), 4.70 (d, J = 1.44 Hz, 2H), 3.70-3.61 (m,2H), 3.06-3.02 (m, 1H), 2.95-2.90 (m, 1H), 2.78-2.70 (m, 1H), 2.68- 2.58(m, 2H), 2.15-2.10 (m, 2H). LCMS: 470.0(m + 1), RT(4.42) min, 99.19%(Max), 98. 81% (254 nm). Intermediate 34 and 4-phenyl-2- thiazolylmethylamine 1-(3-Phenoxy-benzyl)-pyrrolidine-3-carboxylic acid(4-phenyl-thiaz-1-2-ylmethyl)-amide 86

¹H NMR (400 MHz, CD₃OD): δ 7.59 (s, 1H), 7.37-7.31 (m, 3H), 7.13-7.08(m, 2H), 7.01-6.97 (m, 3H), 6.93-6.90 (m, 1H), 6.82 (s, 1H), 3.68-3.68(m, 2H), 3.43- 3.35 (m, 2H), 2.93-2.87 (m, 2H), 2.80-2.74 (m, 3H),2.64-2.58 (m, 2H), 2.09-2.01 (m, 1H), 2.00- 1.98 (m, 1H). Intermediate34 and 2-(1H- imidazol-4-yl)- ethylamine1-(3-Phenoxy-benzyl)-pyrrolidine-3-carboxylic acid[2-(1H-imidazol-4-yl)-ethyl]-amide 87

¹H NMR (400 MHz, DMSO-d₆): δ 7.85-7.84 (m, 1H), 7.40-7.35 (m, 2H),7.33-7.29 (m, 1H), 7.14- 7.10 (m, 1H), 7.07-7.05 (m, 1H), 7.00-6.98 (m,2H), 6.94 (s, 1H), 6.87-6.85 (m, 1H), 3.77-3.70 (m, 2H), 3.58-3.53 (m,3H), 3.10- 3.06 (m, 2H), 2.82-2.80 (m, 1H), 2.74-2.69 (m, 1H), 2.59-2.57(m, 1H), 2.37-2.33 (m, 2H), 1.88- 1.73 (m, 5H), 1.43-1.41 (m, 1H).Intermediate 34 and tetra- hydronfuran- 2ylmethyl amine1-(3-Phenoxy-benzyl)-pyrrolidine-3-carboxylic acid(tetrahydro-furan-2-ylmethyl)-amide 88

¹H NMR (400 MHz, DMSO-d₆): δ 8.42 (s, 1H), 7.40-7.29 (m, 4H), 7.15-7.11(m, 1H), 7.08-7.06 (m, 1H), 7.00-6.98 (m, 2H), 6.95- 6.92 (m, 3H),6.88-6.86 (m, 1H), 4.39 (d, J = 5.80 Hz, 2H), 3.57 (s, 2H), 2.82-2.76(m, 2H), 2.63 (brs, 1H), 2.32 (brs, 2H), 1.89 (d, J = 7.08 Hz, 2H).Intermediate 34 and thiophene2- ylmethyl amine1-(3-Phenoxy-benzyl)-pyrrolidine-3- carboxylic acid(thiophen-2-ylmethyl)-amide 89

¹H NMR (400 MHz, CD₃OD): δ 8.46-8.42 (m, 2H), 7.26-7.28 (m, 1H),7.04-7.02 (m, 2H), 6.94- 6.91 (m, 1H), 4.56-4.48 (m, 4H), 3.66 (d, J =2.04 Hz, 2H), 3.05- 3.01 (m, 1H), 2.92-2.88 (m, 1H), 2.76-2.72 (m, 1H),2.67-2.61 (m, 2H), 2.54 (s, 3H), 2.14-2.09 (m, 2H). LCMS: 409.3(m + 1),RT(3 .01) min, 98.34% (Max), 97.45% (254 nm). Intermediate 33 and5-methyl- pyrazin-2- ylmethyl amine1-[3-(2,2,2-Trifluoro-ethoxy)-benzyl]-pyrrolidine-3- carboxylic acid(5-methyl-pyrazin-2-ylmethyl)-amide 90

¹H NMR (400 MHz, CD₃OD): δ 8.34 (dd, J = 4.88, 1.00 Hz, 1H), 7.63-7.61(m, 1H), 7.29-7.23 (m, 2H), 7.06-7.02 (m, 2H), 6.93- 6.91 (m, 1H),4.54-4.48 (m, 4H), 3.67 (s, 2H), 3.06-3.00 (m, 1H), 2.90-2.85 (m, 1H),2.72-2.65 (m, 3H), 2.34 (s, 3H), 2.18-2.06 (m, 2H). Intermediate 35 and3-methyl- pyridin-2- ylmethyl amine1-[3-(2,2,2-Trifluoro-ethoxy)-benzyl]-pyrrolidine-3- carboxylic acid(3-methyl-pyridin-2-ylmethyl)-amide 91

¹H NMR (400 MHz, CD₃OD): δ 7.35-7.29 (m, 3H), 7.13-7.08 (m, 2H),7.01-6.97 (m, 3H), 6.91- 6.89 (m, 1H), 6.07 (d, J = 2.96 Hz, 1H), 5.91(dd, J = 2.94, 0.92 Hz, 1H), 4.27 (s, 2H), 3.69- 3.61 (m, 2H), 2.97-2.88(m, 2H), 2.79-2.73 (m, 1H), 2.63-2.56 (m, 2H), 2.23 (s, 3H), 2.10-2.04(m, 2H). Intermediate 34 and 5-methyl- furan-2- ylmethyl amine1-(3-Phenoxy-benzyl)-pyrrolidine-3-carboxylic acid(5-methyl-furan-2-ylmethyl)-amide 92

¹H NMR (400 MHz, CD₃OD): δ 8.00-7.96 (m, 1H), 7.69-7.67 (m, 1H),7.55-7.53 (m, 1H), 7.30- 7.26 (m, 1H), 7.04-7.02 (m, 2H), 6.94-6.91 (m,1H), 4.54-4.48 (m, 4H), 3.71-3.63 (m, 2H), 3.09- 3.03 (m, 1H), 2.95-2.91(m, 1H), 2.79-2.71 (m, 1H), 2.69-2.60 (m, 2H), 2.16-2.08 (m, 2H).Intermediate 35 and 6- trifluoromethyl- pyridin-2- ylmethyl amine1-[3-(2,2,2-Trifluoro-ethoxy)-benzyl]-pyrrolidine-3- carboxylic acid(6-trifluoromethyl-pyridin-2- ylmethyl)-amide 93

NMR 400 MHz, DMSO-d₆: δ 8.47-8.49 (m, 1H), 8.41-8.42 (m, 1H), 7.71-7.76(m, 2H), 7.35- 7.39 (m, 2H), 7.29-7.33 (m, 1H), 7.08-7.25 (m, 1H),6.85-7.00 (m, 6H), 5.74 (s, 1H), 4.37-4.38 (m, 2H), 3.59 (s, 2H),2.75-2.82 (m, 2H), 2.62-2.65 (m, 1H), 2.43- 2.47 (m, 1H), 2.20-2.25 (m,1H), 1.18-1.80 (m, 1H). Intermediate 45 and 2- pyridinylmethyl amine3-hydroxy-1-(phenyloxy-benzyl)-pyrrolidine-3- carboxylic acid(pyridin-2-ylmethyl)-amide 94

¹H NMR : 400 MHz, DMSO-d₆: δ 8.48-8.50 (m, 2H), 7.73-7.74 (m, 1H),7.30-7.37 (m, 5H), 6.87-7.14 (m, 6H), 6.60 (s, 1H), 4.38-4.46 (m, 4H),3.28-3.30 (m, 2H), 2.48-2.50 (m, 1H), 1.98- 1.99 (m, 1H). LCMS: 418.2(M + H), Rt. 3.4 min, 97.5% (max), 97.9% (254 nm). Intermediate 56 andpyridine-2- ylmethyl amine3-Hydroxy-2-oxo-1-(3-phenoxy-benzyl)-pyrrolidine- 3-carboxylic acid(pyridin-2-ylmethyl)-amide 95

¹H NMR: 400 MHz, DMSO-d₆: δ 8.95-9.08 (m, 1H), 8.50 (d, J = 4.20 Hz,1H), 7.75-7.75 (m, 1H), 7.30-7.40 (m, 3H), 7.26 (d, J = 1.88 Hz, 1H),6.89-7.15 (m, 7H), 4.36-4.58 (m, 4H), 3.35-3.38 (m, 2H), 2.81-2.89 (m,1H), 2.48- 2.50 (m, 1H). Intermediate 57 and pyridine-2- ylmethyl amine3-Chloro-2-oxo-1-(3-phenoxy-benzyl)-pyrrolidine-3- carboxylic acid(pyridin-2-ylmethyl)-amide 96

¹H NMR (400 MHz, CD₃OD): δ 8.53 (s, 1H), 7.44-7.39 (m, 3H), 7.37-7.31(m, 2H), 7.22-7.10 (m, 5H), 7.07-7.02 (m, 3H), 6.99- 6.62 (m, 1H),4.40-4.33 (m, 2H), 4.17-4.08 (m, 2H), 3.30-3.22 (m, 1H), 3.20-3.12 (m,4H), 2.34- 2.25 (m, 1H), 2.19-2.10 (m, 1H). LCMS: 453.2 (m + 1),RT(4.38) min, 99.57% (Max), 99.40%(220nm). Intermediate 34 and4-difluoro methoxy-benzyl amine 1-(3-Phenoxy-benzyl)-pyrrolidine-3-carboxylic acid 4-difluoromethoxy-benzylamide 97

¹H NMR (400 MHz, CD₃OD): δ 8.31-8.31 (m, 1H), 7.64-7.61 (m, 1H),7.30-7.26 (m, 1H), 7.24- 7.22 (m, 1H), 7.04-7.02 (m, 2H), 6.94-6.91 (m,1H), 4.55-4.50 (m, 2H), 4.48-4.43 (m, 2H), 3.66- 3.62 (m, 2H), 3.06-3.02(m, 1H), 2.93-2.88 (m, 1H), 2.76-2.72 (m, 1H), 2.68-2.58 (m, 2H), 2.34(s, 3H), 2.14-2.03 (m, 2H). Intermediate 35 and 5-methyl- pyridin-2-ylmethyl amine 1-[3-(2,2,2-Trifluoro-ethoxy)-benzyl]-pyrrolidine-3-carboxylic acid (5-methyl-pyridin-2-ylmethyl)-amide 98

¹H NMR (400 MHz, CD₃OD): δ 8.35 (s, 1H), 7.61-7.59 (m, 1H), 7.49-7.45(m, 1H), 7.40 (s, 1H), 7.21-7.16 (m, 3H), 4.64-4.57 (m, 4H), 4.46-4.32(m, 2H), 3.69- 3.54 (m, 3H), 3.32-3.31 (m, 2H), 2.54-2.20 (m, 2H). LCMS:412.3(m + 1), RT(3.19) min, 97.96% (Max), 98.12% (220 nm). Intermediate35 and 3-fluoro- pyridin-2- ylmethyl amine1-[3-(2,2,2-Trifluoro-ethoxy)-benzyl]-pyrrolidine-3- carboxylic acid(3-fluoro-pyridin-2-ylmethyl)-amide 99

¹H NMR (CDCl₃) δ: 8.57-8.30 (m, 2H), 8.03-7.82 (m, 2H), 7.68 (s, 1H),7.47 (td, J = 7.5, 1.8 Hz, 1H), 7.41-7.29 (m, 3H), 7.16-7.07 (m, 1H),7.07-6.96 (m, 1H), 4.72-4.35 (m, 2H), 3.82-3.43 (m, 2H), 3.28-3.00 (m,2H), 2.49 (s, 1H), 2.28- 2.01 (m, 1H), 1.80-1.58 (m, 1H), 1.26 (s, 3H).Intermediate 61 and 2- pyridylbenzy- amine3-Methyl-1-(2-phenyl-oxazol-4-ylmethyl)-pyrrolidine-3- carboxylic acid(pyridin-2-ylmethyl)-amide 100 

¹H NMR (CDCl₃) δ: 7.35-7.12 (m, 3H), 7.10-6.88 (m, 5H), 6.87-6.73 (m,1H), 6.45 (t, J = 5.5 Hz, 1H), 3.95 (dd, J = 7.8, 2.7 Hz, 1H), 3.87-3.77(m, 1H), 3.61 (td, J = 11.4, 2.7 Hz, 1H), 3.43 (dd, J = 13.2, 7.8 Hz,2H), 3.31-3.12 (m, 3H), 2.70-2.48 (m, 1H), 2.07 (td, J = 11.4, 3.3 Hz,1H), 1.91 (t, J = 11.1 Hz, 1H), 1.08 (t, J = 7.3 Hz, 3H) Intermediate 63and ethylamine 4-(3-Phenoxy-benzyl)-morpholine-2- carboxylic acidethylamide 101 

¹H NMR (300 MHz, DMSO-d₆) d: 8.27-8.08 (t, J = 5.2 Hz, 1H), 7.43-7.26(m, 3H), 7.17-6.95 (m, 6H), 6.90-6.82 (ddd, J = 8.1, 2.5, 1.0 Hz, 1H),6.80-6.71 (d, J = 1.2 Hz, 1H), 4.39-4.18 (m, 2H), 3.67-3.43 (m, 5H),2.91- 2.75 (d, J = 9.3 Hz, 1H), 2.65- 2.53 (td, J = 8.7, 5.2 Hz, 1H),2.49-2.37 (m, 1H), 2.30-2.13 (m, 2H), 1.64-1.46 (ddd, J = 13.2, 8.4, 5.4Hz, 1H), 1.23-1.14 (s, 3H). Intermediate 40 and C-(1- Methyl-1H-imidazol-2-yl)- methylamine3-Methyl-1-(3-phenoxy-benzyl)-pyrrolidine-3-carboxylic acid(1-methyl-1H-imidazol-2-ylmethyl)-amide 102 

¹H NMR (300 MHz, DMSO-d₆) δ: 8.48 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 8.28(t, J = 5.8 Hz, 1H), 7.94-7.80 (m, 2H), 7.79-7.66 (m, 2H), 7.54-7.40 (m,3H), 7.29- 7.15 (m, 2H), 4.36 (dd, J = 5.9, 2.3 Hz, 2H), 3.86 (t, J =1.3 Hz, 2H), 2.99 (d, J = 9.2 Hz, 1H), 2.67 (dtd, J = 23.7, 8.6, 5.7 Hz,2H), 2.43-2.23 (m, 2H), 1.60 (ddd, J = 13.2, 8.2, 5.5 Hz, 1H), 1.28 (s,3H). Intermediate 64 and 2- pyridylbenzyl- amine3-Methyl-1-(2-phenyl-thiazol-5-ylmethyl)-pyrrolidine-3- carboxylic acid(pyridin-2-ylmethyl)-amide 103 

¹H NMR (300 MHz, DMSO-d₆) d: 8.49-8.38 (m, 1H), 8.05 (d, J = 7.9 Hz,1H), 7.68-7.53 (m, 1H), 7.43-7.26 (m, 3H), 7.17- 7.03 (m, 2H), 7.03-6.93(dt, J = 7.5, 3.2 Hz, 3H), 6.88 (d, J = 8.1 Hz, 1H), 4.74-4.59 (m, 1H),3.63-3.50 (m, 2H), 2.82 (dd, J = 9.1, 4.7 Hz, 1H), 2.70-2.56 (m, 1H),2.34-2.11 (m, 2H), 1.67 (t, J = 7.3 Hz, 2H), 1.61-1.49 (m, 1H), 1.19 (d,J = 6.2 Hz, 3H), 0.81 (q, J = 7.0 Hz, 3H). Intermediate 40 and1-Pyridin- 3-yl- propylamine3-Methyl-1-(3-phenoxy-benzyl)-pyrrolidine-3- carboxylic acid(1-pyridin-3-yl-propyl)-amide 104 

¹H NMR (CDCl₃) δ: 7.35-7.24 (m, 3), 7.11-6.98 (m, 5), 6.92- 6.87 (m, 1),4.28-4.22 (m, 1), 4.13-4.07 (m, 1), 3.88-3.68 (m, 2), 3.61 (s, 2),3.39-3.10 (br m, 3), 2.99 (s, 3), 2.93-2.75 (m, 2), 2.63-2.44 (m, 2),2.12-2.03 (m, 2) Intermediate 40 and 1-Methyl- piperazin-2-onehydrochloride 1-Methyl-4-[1-(3-phenoxy-benzyl)-pyrrolidine-3-carbonyl]-piperazin-2-one 105 

¹H NMR (300 MHz, CDCl₃) δ 8.55 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 7.64(td, J = 7.7, 1.8 Hz, 1H), 7.61-7.51 (m, 1H), 7.39- 7.14 (m, 5H),7.13-6.93 (m, 5H), 6.86 (ddd, J = 8.1, 2.5, 1.1 Hz, 1H), 4.69-4.41 (m,2H), 4.10 (dd, J = 10.5, 2.7 Hz, 1H), 3.93 (ddd, J = 11.2, 3.3, 1.6 Hz,1H), 3.69 (td, J = 11.3, 2.5 Hz, 1H), 3.59-3.38 (m, 2H), 3.23 (dt, J =11.4, 2.3 Hz, 1H), 2.65 (dd, J = 11.6, 2.0 Hz, 1H), 2.16 (d, J = 3.3 Hz,1H), 2.04 (dd, J = 11.4, 10.5 Hz, 1H). Intermediate 63 and 2-pyridylbenzyl amine 4-(3-Phenoxy-benzyl)-morpholine-2- carboxylic acid(pyridin-2-ylmethyl)-amide 106 

¹H NMR (300 MHz, CDCl₃) δ 7.41-7.22 (m, 3H), 7.16-6.96 (m, 5H), 6.89(ddd, J = 8.2, 2.5, 1.1 Hz, 1H), 4.21 (dd, J = 10.1, 2.5 Hz, 1H), 3.92(ddd, J = 11.2, 3.4, 1.5 Hz, 1H), 3.81-3.36 (m, 11H), 2.91 (dt, J =11.9, 2.1 Hz, 1H), 2.69 (dq, J = 11.6, 2.0 Hz, 1H), 2.40 (dd, J = 11.9,10.1 Hz, 1H), 2.26 (td, J = 11.5, 3.4 Hz, 1H). Intermediate 63 andmorpholine Morpholin-4-yl-[4-(3-phenoxy-benzyl)-morpholin-2-yl]-methanone 107 

¹H NMR (300 MHz, CDCl₃) δ 7.42-7.22 (m, 3H), 7.16-6.97 (m, 5H),6.93-6.82 (m, 2H), 4.05 (dd, J = 10.6, 2.7 Hz, 1H), 3.92 (ddd, J = 11.2,3.3, 1.5 Hz, 1H), 3.69 (td, J = 11.3, 2.5 Hz, 1H), 3.59-3.34 (m, 9H),3.22 (dt, J = 11.4, 2.3 Hz, 1H), 2.67 (dq, J = 11.7, 2.1 Hz, 1H), 2.16(td, J = 11.5, 3.3 Hz, 1H), 2.05- 1.92 (m, 1H). Intermediate 63 and 2-meethoxyethyl amine 4-(3-Phenoxy-benzyl)-morpholine-2- carboxylic acid(2-methoxy-ethyl)-amide 108 

LCMS: 414.5 (m + 1), RT(1.61) min, 91.5% (220nm). Intermediate 40 and2,3- Dihydro-1H- pyrolo[3,4- c]pyridine(1,3-Dihydro-pyrrolo[3,4-c]pyridin-2-yl)-[3-methyl-1-(3-phenoxy-benzyl)-pyrrolidin-3-yl]-methanone 109 

¹H NMR (D₂O) δ 8.73 (d, J = 5.5 Hz, 1H), 8.57 (t, J = 7.8 Hz, 1H),8.06-7.92 (m, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.55 (d, J = 11.6 Hz, 3H),4.53 (s, 2H), 3.95-3.23 (m, 6H), 2.82-2.01 (m, 3H). LCMS: 380 (M + 1),Rt. 2.33 min. HPLC: 95.8% (254 nm), Rt. 2.46 min. Intermediate 35 and2-pyridyl benzylamine1-(3-Trifluoromethoxy-benzyl)-pyrrolidine-3-carboxylic acid(pyridin-2-ylmethyl)-amide hydrochloride

Example 7 3-Methyl-2-oxo-1-(3-phenoxy-benzyl)-piperidine-3-carboxylicacid (pyridin-2-ylmethyl)-amide (110)

3-Methyl-2-oxo-1-(3-phenoxy-benzyl)-piperidine-3-carboxylic acid(Intermediate 51, 0.1 g, 0.29 mmol) was taken in anhydrousdichloromethane (5 mL) along with 2-aminomethyl pyridine (0.045 mL, 0.44mmol) and triethylamine (0.16 mL, 1.17 mmol). The reaction mixture wascooled to 0° C. and propane phosphonic acid anhydride (T3P) (0.28 g,0.88 mmol) was added dropwise. The reaction mixture was stirred for 3 hat ambient temperature. The organic phase was washed with water (2×20mL), dried over anhydrous sodium sulfate and concentrated under reducedpressure to get a crude mass, which was purified by columnchromatography to provide the titled compound as an off white gum (63%,80 mg). LCMS: 430.3 (M+H), Rt. 3.8 min, 97.8% (max), 97.6% (220 nm).NMR: 400 MHz, DMSO-d₆: δ 8.46-8.48 (m, 1H), 8.27 (s, 1H), 7.71-7.72 (m,1H), 7.35-7.39 (m, 2H), 7.27-7.31 (m, 1H), 7.21-7.24 (m, 2H), 7.13-7.15(m, 1H), 6.97-7.02 (m, 3H), 6.85-6.88 (m, 2H), 0.00 (s, 2H), 0.00 (d,J=5.72 Hz, 2H), 3.19-3.22 (m, 2H), 2.29-2.34 (m, 1H), 1.65-1.70 (m, 2H),1.54-1.60 (m, 1H), 1.35 (s, 3H).

Example 8 1-[3-(Pyrrolidine-1-sulfonyl)-benzyl]-pyrrolidine-3-carboxylicacid (4,6-dimethyl-pyridin-2-ylmethyl)-amide hydrochloride (111)

A solution of bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octaneadduct (65.5 mg; 0.26 mmol; 1.50 eq.) and(4,6-dimethylpyridin-2-yl)methanamine (34.5 μl; 0.26 mmol; 1.50 eq.) inanhydrous THF (2.00 ml) was irradiated in the microwave at 130° C. for20 min. A solution of1-[3-(pyrrolidine-1-sulfonyl)-benzyl]-pyrrolidine-3-carboxylic acidmethyl ester (intermediate 68; 60.00 mg; 0.17 mmol; 1.00 eq.) inanhydrous THF (0.5 ml) was added to the reaction mixture and the purplesolution was irradiated in the microwave at 130° C. for 40 min. To thereaction mixture was added methanol (0.5 ml), stirred an additional 10min at room temperature and concentrated under reduced pressure. Theresidue was purified by column chromatography (dichloromethane/methanol0-10%). The pure fractions were concentrated under reduced pressure,dissolved in methanol (2 ml), aqueous 1N hydrochloric acid (168 μl) andwater were added, and lyophilized to give the titled compound as ayellow glassy solid (74 mg, 87%). ¹H NMR (MeOD-d₄) δ 8.08 (s, 1H), 7.96(d, J=7.9 Hz, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.63(d, J=6.3 Hz, 2H), 4.75-4.46 (m, 4H), 3.81-3.34 (m, 5H), 3.27 (ddd,J=6.8, 4.3, 2.7 Hz, 4H), 2.74 (s, 3H), 2.60 (s, 3H), 2.32 (ddd, J=86.5,22.6, 14.0 Hz, 2H), 1.76 (t, J=6.6 Hz, 4H). LCMS: 457 (M+1), Rt. 1.97min. HPLC: 98.8% (254 nm), Rt. 2.26 min.

Example 9 Compound Plate Preparation

Supplied compounds were sent as Assay Ready Plates, with 2 μL per wellof compound in DMSO at 300× the final assay concentrations as describedabove and in the project proposal. All assay plates are stored at in a−80° C. freezer.

On the day of the assay, 198 μL of external solution was added to theappropriate assay plate and mixed thoroughly. This provided a 1:100dilution. A further 1:3 dilution occurred upon addition to the cells inthe IonWorks, giving a 1:300 dilution in total.

On each assay plate, at least 8 wells were reserved for vehicle control(0.3% DMSO) and at least 8 wells for each positive control specific tothe cell line tested. The positive controls were tested in an 8-pointdose response with 3-fold dilutions to determine an IC₅₀ value for eachrun. The positive control compounds are outlined below.

Ion Channel Positive Control & Concentrations

Nav1.6/1.2 Lidocaine: 8, 3-fold dilutions starting at 100 μM

Electrophysiological Recording Solutions

The solutions for recording currents were are follows:

External Recording Solution Internal Recording Solution NaCI 137 mM CsF90 mM KCI 4 mM CsCI 45 mM MgCI₂ 1 mM HEPES 10 mM CaCI₂ 1.8 mM EGTA 10 mMHEPES 10 mM pH 7.3 (titrated with 1M CsOH) Glucose 10 mM p.H 7.3(titrated with 10M NaOH)

Amphotericin B was used to obtain electrical access to the cell interiorat a final concentration of 200 μg/ml in internal recording solution.

Experimental Protocols & Data Analysis Nav Two-Pulse Protocol

Nav currents were evoked by stepping from a holding potential of −120 mVto 0 mV for 2.5 s (pulse 1), followed by a 5 ms inter-pulse interval,and stepping from a holding potential of −120 mV to 0 mV for 20 ms(pulse 2). The voltage protocol was applied (Pre), compounds added,incubated for 300 seconds, and the voltage protocol was applied a finaltime (Post) on the IonWorks Quattro.

Experiment Step Step Duration Start 0 m, 18 s Prime Plate 4 m, 36 s AddCells l m, 45 s Seal Test 8 m, 50 s  Min: −130 mV, Max: −120 mV, Period: 160 ms  Wait 480 s before running the test Obtain Access 12 m,11 s  1. Pause for 1 s  2. Introduce Agent for 70 s  3. Circulate fluidfor 600 s  4. Pause for 60 s Measure Currents 34 m, 34 s  Apply signalonce with no repetitions  Command Voltage time = 11.7876 s  Pre/PostHolding time = 30/1 s;  Sample interval = 0.1 ms  Offset-voltagecorrection (mV):  Pre = 0, Post = 0  Draw compounds from Plate 1:   Nunc384 clear polystyrene   Cat. No. 262160   *Use entire 384 wells   mixcycles: 4, wash cycles: 20 Compound Incubation Time = 300 s Use a“Half-at-Once” scan Pipettor Prewetting: Duration = 30 s  Expel to wasteSolvent Wash at Plate 2:20 wash cycles  Nunc 384 clear polystyrene, Cat. No. 262160 Clean Up 2 m, 29 s Estimated Experiment Time = 64 m, 43s

Nav Data Analysis

The parameters measured were the maximum inward current evoked onstepping to 0 mV from the 1^(st) and 2^(nd) pulse. All data werefiltered for seal quality, seal drop, and current amplitude. The peakcurrent amplitude (Peak) was calculated before (Pre) and after (Post)compound addition to the amount of block was assessed by dividing thePost-compound current amplitude by the Pre-compound current amplitude.These procedures were implemented for the 1^(st) and 2^(nd) pulse.

The data is interpreted according to the following:

Nav1.6 inac Nav1.6 Tonic + >5 μM; + >20 μM; ++ 1-5 μM; ++ 10-20 μM; +++<1 μM. +++ <10 μM. Compound Nav1.6 Nav1.6 number inac Tonic 1 +++ + 2++ + 3 ++ + 4 +++ ++ 5 +++ + 6 + + 7 +++ + 8 +++ + 9 +++ + 10 ++ ++ 11+++ ++ 12 ++ + 13 +++ + 14 + + 15 + + 16 17 ++ ++ 18 + + 19 ++ + 20 + +21 ++ + 22 ++ + 23 ++ + 24 ++ + 25 ++ + 26 ++ + 27 + + 28 +++ + 29 ++ ++30 +++ + 31 ++ + 32 ++ + 33 ++ + 34 ++ + 35 ++ + 36 +++ + 37 ++ + 38 + +39 ++ + 40 +++ ++ 41 +++ ++ 42 + + 43 + + 44 + + 45 + + 46 ++ + 47 ++ +48 ++ + 49 ++ + 50 + + 51 ++ + 52 ++ + 53 ++ + 54 ++ + 55 ++ + 56 ++ +57 ++ + 58 + + 59 + + 60 ++ + 61 + + 62 ++ + 63 + + 64 ++ + 65 +++ + 66+++ ++ 67 +++ ++ 68 ++ ++ 69 +++ + 70 ++ ++ 71 ++ ++ 72 ++ ++ 73 ++ ++74 ++ ++ 75 ++ ++ 76 +++ ++ 77 +++ ++ 78 ++ ++ 79 +++ ++ 80 +++ ++ 81+++ ++ 82 +++ ++ 83 ++ + 84 +++ ++ 85 ++ + 86 + 87 +++ +++ 88 +++ + 89++ + 90 ++ + 91 + + 92 ++ + 93 ++ + 94 ++ + 95 + + 96 + + 97 + + 98 + +99 ++ + 100 ++ ++ 101 ++ + 102 ++ + 103 + + 104 ++ + 105 ++ + 106 + +107 ++ + 108 ++ + 109 +++ ++ 110 +++ ++ 111 ++ +

Example 10 Pharmaceutical Preparations

(A) Injection vials: A solution of 100 g of an active ingredientaccording to the invention and 5 g of disodium hydrogen phosphate in 3 lof bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid,sterile filtered, transferred into injection vials, is lyophilized understerile conditions and is sealed under sterile conditions. Eachinjection vial contains 5 mg of active ingredient.

(B) Suppositories: A mixture of 20 g of an active ingredient accordingto the invention is melted with 100 g of soy lecithin and 1400 g ofcocoa butter, is poured into moulds and is allowed to cool. Eachsuppository contains 20 mg of active ingredient.

(C) Solution: A solution is prepared from 1 g of an active ingredientaccording to the invention, 9.38 g of NaH₂PO₄.2 H₂O, 28.48 g ofNa₂HPO₄.12 H₂O and 0.1 g of benzalkonium chloride in 940 ml ofbidistilled water. The pH is adjusted to 6.8, and the solution is madeup to 1 l and sterilized by irradiation. This solution could be used inthe form of eye drops.

(D) Ointment: 500 mg of an active ingredient according to the inventionis mixed with 99.5 g of Vaseline under aseptic conditions.

(E) Tablets: A mixture of 1 kg of an active ingredient according to theinvention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and0.1 kg of magnesium stearate is pressed to give tablets in aconventional manner in such a way that each tablet contains 10 mg ofactive ingredient.

(F) Coated tablets: Tablets are pressed analogously to Example E andsubsequently are coated in a conventional manner with a coating ofsucrose, potato starch, talc, tragacanth and dye.

(G) Capsules: 2 kg of an active ingredient according to the inventionare introduced into hard gelatin capsules in a conventional manner insuch a way that each capsule contains 20 mg of the active ingredient.

(H) Ampoules: A solution of 1 kg of an active ingredient according tothe invention in 60 l of bidistilled water is sterile filtered,transferred into ampoules, is lyophilized under sterile conditions andis sealed under sterile conditions. Each ampoule contains 10 mg ofactive ingredient.

(I) Inhalation spray: 14 g of an active ingredient according to theinvention are dissolved in 10 l of isotonic NaCl solution, and thesolution is transferred into commercially available spray containerswith a pump mechanism. The solution could be sprayed into the mouth ornose. One spray shot (about 0.1 ml) corresponds to a dose of about 0.14mg.

While a number of embodiments of this invention are described herein, itis apparent that the basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

We claim:
 1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein: Z¹ is C(R)(R),C(O), C(S), or C(NR); Z² is C(R)(R), O, S, SO, SO₂, or NR; X is —O—,—S—, —SO₂—, —SO—, —C(O)—, —CO₂—, —C(O)N(R)—, —NRC(O)—, —NRC(O)N(R)—,—NRSO₂—, or —N(R)—; or X is absent; A is a C₁₋₆ aliphatic, C₅₋₁₀ aryl, a3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7membered heterocylic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur; each of which is optionally substituted; R¹ is —R, halogen,-haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂,—NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂; each of R², R³, R⁴, and R⁵,is independently H or C₁₋₆ aliphatic; Y is —CH₂—, —O—, —S—, —SO₂—, —SO—,—C(O)—, —CO₂—, —C(O)N(R)—, —NRC(O)—, —NRC(O)N(R)—, —NRSO₂—, or —N(R)—;Ring B is C₅₋₁₀ aryl or a 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of which is optionally substituted; each R⁶ is independently —R,halogen, -haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R,—C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂; m is 0, 1, 2, or3; n is 0, 1, 2, or 3; q is 0, 1, 2, or 3; r is 1 or 2; and each R isindependently hydrogen, C₁₋₆ aliphatic, C₅₋₁₀ aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted; or two Rgroups on the same atom are taken together with the atom to which theyare attached to form a C₃₋₁₀ aryl, a 3-8 membered saturated or partiallyunsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, ora 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each of whichis optionally substituted.
 2. The compound of claim 1, wherein X is —O—,—C(O)—, —CO₂—, or —C(O)NH—, or X is absent.
 3. The compound of claim 1,wherein A is methyl or ethyl.
 4. The compound of claim 1, wherein A isC₃₋₁₀ aryl, a 3-8 membered saturated or partially unsaturatedcarbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a 5-6membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; each of which is optionallysubstituted.
 5. The compound of claim 4, wherein A is selected from thefollowing:


6. The compound of claim 1, wherein R¹ is H.
 7. The compound of claim 1,wherein R¹ is F, Cl, or OH.
 8. The compound of claim 1, wherein Y is—CH₂—.
 9. The compound of claim 1, wherein Ring B is selected from:


10. The compound of claim 9, wherein each R⁶ is independently halogen,—OR, —SR, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂.
 11. The compound of claim 1, offormula III,

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1, of formula V,

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim1, of formula VI,

or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1, selected from Examples 1-111.
 15. A pharmaceutical compositioncomprising a compound of claim 1, and a pharmaceutically acceptableadjuvant, carrier, or vehicle.
 16. A method for inhibiting Nav1.6activity in a patient or in a biological sample, comprising the step ofadministering to said patient or contacting said biological sample witha compound of claim 1 or a physiologically acceptable salt thereof. 17.A method for treating a Nav1.6-mediated disorder in a patient in needthereof, comprising the step of administering to said patient a compoundof claim
 1. 18. The method of claim 17, wherein the disorder is multiplesclerosis (MS), polyneuritis, multiple neuritis, amyotrophic lateralsclerosis (ALS), Alzheimer's disease or Parkinson's disease
 19. A methodfor treating multiple sclerosis (MS) in a subject, comprising the stepof administering to said subject a compound of claim 1 or aphysiologically acceptable salt thereof.
 20. A process for manufacturinga compound of formula I according to claim 1, comprising the steps of:reacting a compound of formula (A):

wherein PG is H or a protecting group, and X, A, R¹, R², R³, R⁴, R⁵, m,and n, are as defined in claim 1; with a compound of formula (B):

wherein Y′ is an electrophilic group, and ring B, R⁶, and q are asdefined in claim 1; to yield a compound of formula I.